Sleep Disturbances: Managing Parasomnias Bpac Better Medicine EDITOR-IN-CHIEF Professor Murray Tilyard

SLEEP APNOEA | PARASOMNIAS | SYRINGE DRIVERS | INTERMEDIATE HYPERGLYCAEMIA

www.bpac.org.nz Issue 48 November 2012

nz Sleep disturbances: managing parasomnias bpac better medicine EDITOR-IN-CHIEF Professor Murray Tilyard

EDITOR Rebecca Harris Issue 48 November 2012

PROGRAMME DEVELOPMENT Gareth Barton, Lucy Broughton, Mark Caswell, Rachael Clarke, Peter Ellison, Dr Hywel Lloyd, Dr Lik Best Practice Journal (BPJ) Loh, Kirsten Simonsen, Dr Sharyn Willis ISSN 1177-5645 nz REPORTS AND ANALYSIS BPJ is published and owned by bpac Ltd Justine Broadley, Todd Gillies, Andy Tomlin Level 8, 10 George Street, Dunedin, New Zealand.

DESIGN Bpacnz Ltd is an independent organisation that promotes Michael Crawford health care interventions which meet patients’ needs and WEB are evidence based, cost effective and suitable for the New Gordon Smith, Kyi Thant Zealand context. We develop and distribute evidence based resources which MANAGEMENT AND ADMINISTRATION describe, facilitate and help overcome the barriers to best Kaye Baldwin, Tony Fraser, Kyla Letman practice. CLINICAL ADVISORY GROUP Bpacnz Ltd is currently funded through contracts with Professor John Campbell, Leanne Hutt, Dr Rosemary PHARMAC and DHB Shared Services. Ikram, Dr Cam Kyle, Dr Liza Lack, Dr Chris Leathart, nz Janet Mackay, Natasha Maraku, Dr Peter Moodie, Bpac Ltd has five shareholders: Procare Health, Barbara Moore, Associate Professor Jim Reid, South Link Health, General Practice NZ, the University of Otago and Pegasus Health. Associate Professor David Reith, Leanne Te Karu, Professor Murray Tilyard

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SOUTH LINK We would like to acknowledge the following people HEALTH for their guidance and expertise in developing this edition: Dr Alex Bartle, Christchurch Dr Emma Best, Auckland The information in this publication is specifically designed to address conditions and requirements in New Zealand and no other country. BPAC NZ Dr Simon Briggs, Auckland Limited assumes no responsibility for action or inaction by any other party Suzanne Brocx, Northland based on the information found in this publication and readers are urged to Helen Cleaver, Dunedin seek appropriate professional advice before taking any steps in reliance on Dr Kirsten Coppell, Dunedin this information. Dr Shaun Costello, Dunedin Printed in New Zealand on paper sourced from well-managed sustainable Dr Michael Hlavac, Christchurch forests using mineral oil free, soy-based vegetable inks Dr Chris Lewis, Auckland Dr Brandon Orr-Walker, Auckland

CONTACT US: Mail: P.O. Box 6032, Dunedin Email: [email protected] Phone: 03 477 5418 Free-fax: 0800 27 22 69 www.bpac.org.nz CONTENTS

Issue 48 November 2012

6 6 Obstructive sleep apnoea in adults Obstructive sleep apnoea affects many adults in New Zealand, and is especially common among Māori and Pacific peoples. Moderate to severe obstructive sleep apnoea is associated with a significant risk of cardiovascular morbidity and mortality, along with an increased risk of motor vehicle accidents, due to daytime sleepiness and fatigue. In most cases, an overnight sleep study is required to confirm the diagnosis. Continuous positive airway pressure (CPAP) devices are the mainstay of treatment.

Sleep disturbances: managing parasomnias in 16 16 general practice The term “parasomnia” describes a group of sleep disorders associated with unnatural movements, behaviours, emotions, perceptions and dreams that occur while falling asleep, during sleep, between sleep stages or upon waking. Most people experience a parasomnia during their lifetime. In the majority of cases, parasomnias are benign and, although frightening, no cause for concern. Reassurance, advice on methods to maximise sleep (sleep hygiene) and making the sleep environment safe are the key factors in managing people with parasomnias.

28 When and how to use a syringe driver in palliative 28 care Syringe drivers are often required to provide medicines for symptom management in patients who are terminally ill. They provide continuous subcutaneous administration of medicines to enable effective symptom control when medicines given by other routes are inappropriate or no longer effective. With guidance and support from the local hospice or district nursing services, General Practitioners can arrange a syringe driver infusion for a patient in their home or in a residential care facility, prescribe and monitor the appropriate mix of medicines and manage breakthrough symptoms.

BPJ Issue 48 1 CONTENTS

Issue 48 November 2012

Initiating interventions in people with intermediate 36 36 hyperglycaemia (“pre-diabetes”) Intermediate hyperglycaemia is a biochemical state in which a person has glucose levels above the normal range, but does not yet meet the criteria for a diagnosis of diabetes. The primary aim of management of intermediate hyperglycaemia is to prevent progression to diabetes. Intervention involves structured lifestyle changes, and for people with a high risk of progression to diabetes who do not achieve normoglycaemia, treatment with metformin.

3 Upfront Lung cancer in New Zealand: overcoming barriers

25 News and updates Update on azithromycin: new prescriber information and availability

42 Using the New Zealand Formulary Are you getting the most from the NZF? Resources for getting started

44 Correspondence Recommended ceftriaxone dose for gonorrhoea now 500 mg IM stat • The role of digital rectal examination in prostate cancer follow-up • Heterophile antibody vs EBV serology testing for glandular fever

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2 BPJ Issue 48 UPFRONT

Lung cancer in New Zealand: overcoming barriers

Lung cancer is the leading cause of cancer death in New Procare and Tamaki PHOs; and the University of Auckland. The Zealand. In 2004, Dr Wendy Stevens, from the University research included an audit of patients diagnosed with lung of Auckland, conducted an audit of lung cancer care, from cancer in 2008, from initial presentation to treatment, patient presentation in secondary care to treatment. At this time, five interviews, General Practitioner focus groups and primary year survival from lung cancer was 10.2% in New Zealand, and secondary care provider surveys. The 2008 audit findings compared to 13% in Australia and 15% in the United States. were very similar to 2004 – patients were more commonly presenting acutely to secondary care (rather than via a primary The audit revealed a number of disturbing findings: care referral) and presenting with advanced disease. Slower More patients presented to secondary care via an acute work-up times were encountered for outpatients/early stage admission (36%) rather than as an outpatient referral to patients. respiratory medicine via their General Practitioner (29%) Patients presenting via the emergency department more As a result of these findings, it was recommended that systems often had advanced, incurable disease be developed to expedite the diagnosis of patients with early stage disease, such as day-stay or “rapid access” clinics. Of Diagnosis and treatment was often subject to lengthy the patients who presented directly to secondary care, 60% delays, particularly noticeable in outpatients (often with had seen their General Practitioner within the preceding six potentially curable disease) months, which suggests there may be an opportunity for Only 28% of patients were presented at a thoracic earlier diagnosis. Patients interviewed or in focus groups (who multidisciplinary meeting (considered to be the gold had presented to hospital with advanced disease) tended standard approach to management) to feel that most of the delays in the lung cancer pathway Rates of delivery of anti-cancer treatments (surgery, occurred in primary care, although in fact the median time radiotherapy, chemotherapy) were low, and below those from presentation to referral for the whole study population in comparable countries was quite short overall. Māori were 2.5 times more likely to have locally advanced disease, and four times less likely to receive curative The 2008 audit found that the percentage of patients that treatment than Europeans (multi-variate analysis) were presented at a thoracic multidisciplinary meeting had improved to 56%. It has subsequently been recommended When the four Cancer Networks were formed in New Zealand, that all cases of lung cancer should be discussed at a these sobering findings helped to ensure that lung cancer was multidisciplinary meeting. chosen as the first tumour with a dedicated “project stream”. This brought together relevant clinicians to try to improve the Other key findings from the 2008 study are given in Table 1 lung cancer pathway for people in New Zealand. (over page), along with solutions and recommendations.

In 2007, a multidisciplinary study, funded by the Health One of the key issues highlighted from the 2008 study is use Research Council, was set up and lead again by Dr Wendy of radiology services in primary care. It was found that, on Stevens. The study, entitled “Barriers to the timely diagnosis presentation to secondary care, only 64% of patients had and management of lung cancer and description of best undergone chest x-ray examination. Chest x-ray was, however, practice solutions”, involved a number of healthcare providers, often a strong pointer either to a diagnosis of lung cancer including Auckland, Counties Manukau and Lakes DHBs; or to a referral to secondary care, where lung cancer was

BPJ Issue 48 3 subsequently diagnosed. The New Zealand Guidelines Group responses to treatments such as conventional chemotherapy. guidelines for cancer diagnosis outline referral criteria for lung Such changes would help to streamline the patient journey, cancer. However, in the surveys and focus groups, General and improve patient and family/whānau satisfaction with Practitioners felt that these referral criteria were not helpful. care received along that journey. However, it is important to also actually measure patient and family/whānau satisfaction So where to from here? directly, as a “one size fits all” approach may not be appropriate Implementation of the recommendations from this study is in all settings or cultures. likely to make some difference in lung cancer survival rates, but not a large difference. This is due to the intrinsic nature of lung There are also other developments and strategies which may cancer (often asymptomatic until a late stage) and the poor reduce deaths from lung cancer in the future.

Table 1: Key findings and solutions from “Barriers to the timely diagnosis and management of lung cancer and description of best practice solutions”

Finding Solution and/or recommendation

Pacific peoples more commonly presented with metastatic Social marketing campaigns – ongoing rather than one off, disease and were more commonly referred for acute national, targeted to and developed in conjunction with admission. Māori and Pacific peoples. Māori and Pacific peoples were more likely than Europeans to Development of information resources – particularly targeted not attend appointments or initially decline investigation or to Māori and Pacific peoples. referral.

Delays documented in the clinical records occurred due to “Aunties” (primary care coordinators). system factors (10%) such as lost referrals or lack of follow up Secondary care coordinators/lung cancer nurses. of abnormal results, or to patient factors (10%) such as not attending appointments or declining investigation/referrals. Systems/safety nets to follow-up incidental findings and abnormal results. Patients felt that the worst part of the pathway was waiting for investigations and appointments, coupled with lack of Obtain formal feedback from patients and their whānau/ information, particularly leading up to diagnosis. family.

The most common presenting symptom of lung cancer was Upskilling of General Practitioners and primary care workers, cough (49%); only 15% had haemoptysis. by respiratory team. At initial presentation, General Practitioners took specific Improve utilisation of chest x-rays (lower threshold for action, e.g. chest x-ray or referral, for 50% of patients with ordering); have defined guidelines in a user-friendly format. lung cancer. For the other 50%, the General Practitioner’s index of suspicion was not raised, usually because of co-morbidities.

Spirometry was rarely recorded in primary care notes. Risk assessment – recording smoking status accurately Smoking status was not well recorded, particularly for (including dose in pack-years). ex-smokers. Better access to spirometry for General Practitioners.

General Practitioners referred patients to secondary care E-referral systems (rather than fax) with regionally consistent by a wide variety of ways (mainly paper-based such as fax) investigation and referral pathways. and were not informed of their patient’s progress along Expedite investigations and specialist assessment; systematic the pathway. Referrals sometimes got lost leading to approach to action referrals to secondary care in a timely and delays as well as frustration. Although General Practitioners appropriate manner. complained about the difficulty obtaining a timely specialist appointment, the median time from referral to first specialist Improve communication between primary and secondary appointment was 11 days, suggesting that information about care, and with the patient/family/whānau. secondary care services was lacking.

4 BPJ Issue 48 Targeted chemotherapy screening studies have also failed to evaluate whether smokers The molecular nature of lung cancer is being explored, and would be willing to participate in screening outside of the oral treatments have been developed to target any specific context of research trials – unlike successful “whole population” mutations present. In New Zealand, the tyrosine kinase screening programmes such as cervical smears, smokers are a inhibitors gefitinib and erlotinib, which target epidermal subgroup who are already engaging in risky behaviour. growth factor receptor, have been made available for suitable patients. As yet, only a minority of patients have been identified Tobacco control with such mutations and therefore have a good response to Ultimately, prevention of lung cancer would be the best these medicines. These patients do better with the targeted strategy. Effective treatments for smoking cessation in primary medicines than with conventional chemotherapy, and usually care include brief advice or more intensive counselling, nicotine have fewer adverse effects. However, these medicines are also replacement therapy (NRT), buproprion and varenicline. The expensive, and resistance develops, eventually leading to Aspire 2025 project aims to support the government objective disease relapse or progression. of making New Zealand tobacco free by 2025, via research into a number of potential smoking cessation and tobacco control Minimally invasive surgery strategies. Lobectomy may now be performed thoracoscopically, which has a longer procedure time but is associated with reduced Further information about Aspire 2025 is available from: post-operative pain, shorter hospital stay and faster recovery. www.aspire2025.org.nz This may enable older patients or patients previously considered “marginal” to undergo resection. The shorter Overall, this is a rapidly evolving time in lung cancer care. Dr recovery times may also enable adjuvant chemotherapy to be Stevens’ studies have helped to enable significant progress to more consistently delivered to those who may benefit (large be made in offering quality lung cancer services, earlier and Stage 1B, and Stage 2 and 3A tumours). more rapid diagnosis and staging, and more effective and less toxic treatment. It is to be hoped that such advances in Screening local care and international practice will translate into reduced The fundamental problem with screening for lung cancer is the morbidity and mortality from lung cancer in New Zealand in very high false positive rate – small nodules are very commonly the coming years. found on chest CT scans, and most turn out to be benign. A 2010 meta-analysis suggested that if 1000 asymptomatic Detailed reports on “Barriers to the timely diagnosis and smokers were screened with CT, nine curable Stage 1 lung management of lung cancer and description of best practice cancers would be found but also 235 “false positive” nodules solutions” are available from: would be found, many of which would require follow up to www.northerncancernetwork.org.nz ensure they were benign; four thoracotomies would also be performed for what turned out to be a benign process.1 “Recommendations to expedite the diagnosis of lung cancer”, the final report of the HRC_DHBNZ funded project was The United States NLST trial found that CT screening at zero, released in July, 2012 and is also available at the above web one and two years led to a relative reduction in death from address. It contains a number of recommendations that are lung cancer of 20% compared to chest x-ray screening.2 specific to primary care. An article on these recommendations Although there was no control group with “no screening” in will appear in a future edition of Best Practice Journal. this study, these findings suggest that chest x-ray screening of asymptomatic smokers in primary care is not useful. ACKNOWLEDGEMENT: Thank you to Dr Chris Lewis, Respiratory Physician, Auckland District Health Board, Questions remain about the cost effectiveness of lung Chair, Lung Tumour Stream, Northern Cancer Network cancer screening, especially compared to smoking cessation for contributing this article. strategies. The NLST targeted current or ex-smokers with >15 pack-years; however, recent evidence suggests a common 1. Gopal M, Abdullah S, Grady J, Goodwin J. Screening for lung cancer genetic susceptibility shared between COPD/emphysema and with low-dose computed tomography: a systematic review and lung cancer. Future research needs to find a better definition meta-analysis of the baseline findings of randomized controlled trials. J Thorac Oncol 2010;5(8):1233-9. of the highest risk group of smokers, with algorithms which 2. Neugut A, Accordino M. Review: CT screening for lung cancer reduced may include spirometry, presence of emphysema on CT, family mortality in 1 large trial but not in 2 smaller trials. Ann Intern Med history and possibly evaluation of genetic susceptibility. Many 2012;157(6):JC3-6.

BPJ Issue 48 5 Obstructive sleep apnoea in adults

6 Obstructive sleep apnoea is reported to affect 4% of adult males and 2% of adult females. In New Zealand, it is twice as common in Māori adults males compared to non-Māori. Moderate to severe obstructive sleep apnoea is associated with a significantly increased risk of cardiovascular morbidity and mortality. People with mild symptoms and an absence of risk factors can often be managed with lifestyle interventions. However, people with more significant symptoms, such as excessive daytime sleepiness, will usually require treatment with a continuous positive airway pressure (CPAP) device.

Obstructive sleep apnoea is common in adults Apnoea-hypopnoea index Obstructive sleep apnoea is a sleep-related breathing disorder resulting in recurrent, partial (hypopnoea) or complete The severity of obstructive sleep apnoea is quantified by (apnoea) obstruction of the upper airways. It is caused by recording the number of pauses in breathing each hour relaxation of airway muscles during sleep which allows soft that last longer than ten seconds. This is referred to as the tissue in the pharynx to collapse and block the upper airway. apnoea-hypopnoea index (AHI). As a result of not breathing, oxygen saturation levels in the blood rapidly fall, and carbon dioxide increases, and eventually Table 1: Classification of the severity of obstructive sleep the brain triggers a brief arousal to resume breathing. Pauses apnoea2 in breathing usually last between ten and 30 seconds, but may persist for one minute or more. This cycle of events can Obstructive sleep Apnoea-hypopnoea occur hundreds of times a night and leads to broken, poor apnoea severity index (AHI) quality sleep. This night time “marathon” causes daytime sleepiness, which is the characteristic feature of obstructive Normal Less than 5 1 Recurrent hypoxaemia also sleep apnoea syndrome (OSAS). Mild 5 – 15 results in negative health consequences such as cardiovascular morbidity and mortality. Moderate 16 – 30

Severe > 30 Upper airway resistance syndrome and central sleep apnoea are less common than obstructive sleep apnoea, but may be associated with similar symptoms. People with upper airway Traditionally, the AHI is determined following a full resistance syndrome do not experience airway blockage, sleep study carried out in an attended sleep laboratory however, they are frequently aroused from sleep due to the (polysomnography). However, partial studies conducted increased work required to breathe. Central sleep apnoea is by appropriately trained sleep technicians in the patient’s caused by instability or imbalance in the control mechanisms home can accurately diagnose obstructive sleep apnoea that drive respiration. This causes respiration to cycle between in the majority of patients. apnoea and hyperpnoea (deep breaths). Referral to a sleep physician is generally required to differentiate upper airway resistance syndrome and central sleep apnoea from OSAS.

BPJ Issue 48 7 How common is obstructive sleep apnoea in New existing coronary artery disease, diabetes and obesity add to 10 Zealand? this risk. A large study found that, following adjustment for known risk factors, e.g. BMI, people with mild and moderate The prevalence of OSAS in New Zealand is reported to be obstructive sleep apnoea had an approximately two and three- 4% in adult males and 2% in adult females.1 However, rates fold respectively, increased risk of hypertension compared to are elevated among Māori and Pacific peoples. Obstructive people without sleep apnoea.11 Treatment of OSAS in people sleep apnoea is twice as common in Māori males compared with severe disease has been reported to result in a reduction to non-Māori males.3 Māori and Pacific peoples also tend to in arterial blood pressure of approximately 4 mmHg, and may present with more severe forms of OSAS and increased co- improve some cardiac dysfunction, although further trials are morbidities.3 Higher rates of obesity among Māori and Pacific needed.10, 12 Insulin resistance and abnormal lipid metabolism peoples is thought to be the principle reason for the increased have also been independently associated with obstructive prevalence of OSAS in these ethnic groups.4 sleep apnoea.5 Both of these factors are likely to further increase the cardiovascular risk of people with OSAS.5

Obesity is a major risk factor for obstructive sleep apnoea Motor vehicle and occupational accidents are increased in Between 40 – 90% of people with OSAS are obese.2, 5 Obesity people with OSAS due to impaired cognitive function caused increases the risk of OSAS because excess fat tissue around by disrupted sleep. A study of over 900 adults undergoing the neck exerts pressure on the upper airways, increasing the sleep assessment in the United States found that males with likelihood of upper airway collapse occurring during sleep.3 mild sleep apnoea had a four-fold increased risk of having Abdominal obesity has also been shown to reduce lung a motor vehicle accident compared to people without a volumes, which can further increase the risk of upper airway sleep-breathing disorder.13 A small study of 40 injured drivers collapse.6 It has been estimated that a 1 kg/m2 increase in admitted to the Wellington Hospital Emergency Department BMI in a person who is obese, results in a 30% increase in the (mean age 44 years) found that over one-third had obstructive relative risk of clinically significant sleep apnoea occurring in sleep apnoea.14 The rate of traffic accidents involving people the next four years.7 Sleep loss caused by OSAS is also likely to with OSAS has been reported to be significantly reduced after further contribute to obesity. treatment for OSAS.12

Smoking is also associated with an increased prevalence of OSAS, and alcohol use can increase sleep apnoea duration, Clinical features of obstructive sleep apnoea possibly by reducing muscle tone.2 The clinical features of OSAS can be divided into symptoms that occur when the patient is either awake or asleep (Table The incidence of OSAS is increased in people with 2). hypothyroidism and females with polycystic ovary syndrome. The severity of untreated sleep apnoea may be worsened in Table 2: Symptoms of OSAS males using testosterone supplementation. Awake During sleep

Severe obstructive sleep apnoea increases mortality risk Excessive day time Snoring sleepiness Moderate to severe obstructive sleep apnoea is independently Witnessed apnoeas associated with an increased risk of all-cause mortality. A study Lack of concentration Non-refreshing sleep of more than 77 000 patients found that increasing OSAS Cognitive deficits Choking severity was associated with increasing all-cause mortality in Changes in mood Restlessness patients aged younger than 50 years, after adjustments were Morning headaches Vivid dreams made for BMI and age.8 This elevated risk has been estimated Dry mouth to be equivalent to an increase in age of 17.5 years or a 29 Gastroesophageal reflux mmHg increase in mean arterial blood pressure.9 Decreased libido or Insomnia and frequent impotence awakenings Obstructive sleep apnoea is associated with increased Nocturia cardiovascular risk. A predominant feature of OSAS is chronic, Hypersalivation intermittent hypoxia, which is associated with the development Diaphoresis (sweating) of hypertension and hypertensive cardiomyopathy. Co-

8 BPJ Issue 48 Generally all people with obstructive sleep apnoea snore.2 But not all people who snore have sleep apnoea (see “Snoring alone is not a good predictor”). Snoring alone is not a good predictor of obstructive sleep apnoea Excessive daytime sleepiness and witnessed apnoeas are Snoring is caused by the vibration of the soft palate and the symptoms most suggestive of obstructive sleep apnoea. throat during inspiration. It affects between 20 – 60% Partners who have witnessed apnoeas report a sudden halt to of the adult population, and is a frequent cause of snoring followed by a loud snort and resumption of snoring.2 relationship strain.15 However, because snoring is so Sleep apnoeas are more commonly reported by the partners common among otherwise healthy people, it is not a of males.2 Females with obstructive sleep apnoea often report good predictor of OSAS. Snoring may also be associated constant fatigue and lack of energy.2 with obesity, nasal congestion, craniofacial abnormalities, hypothyroidism, acromegaly and soft tissue hypertrophy Assessment tools for suspected obstructive within the palate. Severe snoring has been linked to sleep apnoea hypertension, cardiovascular disease and cerebrovascular The Epworth Sleepiness Score (ESS) is a subjective assessment disease. However, it is not known if snoring itself is an of daytime sleepiness. It is recommended that this score is independent risk factor for cardiovascular disease. calculated prior to referral for sleep testing. Patients are asked to assign a numerical value to each of the following situations Snoring can often be reduced with lifestyle interventions, to indicate the likelihood that they might fall asleep: such as weight reduction (if overweight), avoiding 1. Sitting and reading alcohol, smoking and avoiding sleeping on the back. If lifestyle measures such as these do not result in reduced 2. Watching television snoring, oral appliances such as a mandibular splint or 3. Sitting in a public place, e.g. a theatre or meeting assessment for surgical tightening of the soft palate may 4. As a passenger in a car for an hour be considered.16 5. Lying down to rest in the afternoon 6. Sitting while conversing 7. Sitting after lunch (without alcohol) 8. As a passenger in a car stopped in traffic for a few minutes

Score: 0 = would never sleep, 1 = a slight chance of sleeping, 2 = a moderate chance of sleeping, 3 = a high chance of sleeping. A total score greater than ten is considered abnormal and a score greater than 16 indicates pathological daytime sleepiness.

The British Lung Foundation has an online version of the Epworth Sleepiness Score available at: www.blf.org.uk/Page/ Obstructive-Sleep-Apnoea

The Mallampati score can be used to assess the degree of airway obstruction. Decreased upper airway size is associated with increased sleep apnoea prevalence and is more likely in people who are obese or who have anatomical abnormalities such as a large tongue, or enlarged tonsils, airway walls or soft tissue.5 To determine the Mallampati score, ask the patient to protrude their tongue, assess the visibility of the tonsils, uvula and soft palate and classify according to the degree of obstruction (Figure 1). A Mallampati score of class III or IV is useful for predicting obstructive sleep apnoea severity due to soft palate and tongue abnormalities.17

BPJ Issue 48 9 Sleep apnoea prediction tools There are several tools available to stratify the likelihood of Excessive daytime sleepiness can be a a patient having severe obstructive sleep apnoea. However, symptom of other disorders these should be used as a guide only, as they do not provide sufficient information to make definitive decisions about Simple causes should be considered first when referral or treatment urgency for individual patients. encountering a patient with excessive daytime sleepiness. Lifestyle factors in the patient’s history should be The adjusted neck circumference calculation (Table 3) can be explored to uncover insufficient sleep, primary insomnia used to assess the probability of a patient having obstructive and secondary causes of insomnia, such as depression sleep apnoea, but it does not categorise potential severity. or anxiety. Circadian rhythm disorders, e.g. jet lag, shift work or delayed sleep phase syndrome, and sedating The OSA50 screening questionnaire combined with medicines should also be excluded. overnight pulse oximetry can be used in patients in a primary care setting to rule out moderate to severe obstructive sleep Chronic conditions such as cardiac, respiratory or apnoea. This tool relies on access to an electronic pulse neuromuscular diseases can cause fatigue, hypoventilation oximeter with data recording functionality (or referral to a and daytime sleepiness. Carbon dioxide retention due to private sleep clinic). The process involves asking the patient hypoventilation associated with severe obesity, central specific questions (Table 4), and for patients who score five hypoventilation syndrome, or chronic obstructive or more, arranging overnight pulse oximetry (equivalent pulmonary disease can result in increased daytime to a level IV sleep study – see “Sleep studies”). Patients who sleepiness, which may or may not be accompanied by experience 16 or more occurrences per hour of a 3% drop in breathlessness. oxygen saturation, are suspected to have moderate to severe sleep apnoea.19 The positive predictive value for the OSA50 tool Unusual causes of excessive daytime sleepiness are (questionnaire and oximetry) is 55 – 65%, i.e. the patient has considered last and are usually suggested by specific moderate to severe sleep apnoea, and the negative predictive clinical features. Endocrine disorders, e.g. hypothyroidism, value is 97 – 99%, i.e. they have mild sleep apnoea or no sleep adrenal insufficiency or diabetic ketoacidosis, and apnoea.19 The greatest value of this approach is therefore in neurological causes of drowsiness, e.g. subdural ruling out moderate to severe obstructive sleep apnoea.19 haematoma, encephalitis or intracranial neoplasm, may be a consideration, especially when the presentation does not fit well with OSAS. Refer patients with suspected obstructive sleep apnoea for a sleep study OSAS frequently occurs in conjunction with other sleep For most patients, an overnight sleep study (see “Sleep disorders such as periodic limb movement of sleep studies”) is required to confirm a diagnosis of obstructive sleep (including restless leg syndrome), primary insomnia and apnoea. In New Zealand, there is an absence of nationally narcolepsy. agreed referral criteria for this service and availability is the limiting factor in determining when a patient receives a For further information see: “Sleep disturbances: publicly funded sleep assessment. managing parasomnias in general practice” Page 16. For information about availability of sleep clinic services, contact your local DHB.

Patients at high-risk should be promptly referred for testing, e.g. sleepy drivers with a history of a sleep-related accident or near- miss, occupational drivers or machine operators. Sleepiness should be assessed using the Epworth Sleepiness Score (Page 9). Co-morbidities such as hypertension, cardiovascular disease and diabetes should also influence the urgency of referral.

Patients who do not report daytime sleepiness may not benefit from referral as treatment is aimed primarily at

10 BPJ Issue 48 Class I Class II Class III Class IV

Figure 1: The Mallampati classification for airway obstruction

Table 3: Adjusted neck circumference calculation to assess probability of sleep apnoea, adapted from Skjodt, 200818

Measure + Add = Adjusted neck circumference*

Neck circumference 3 cm for snoring history < 43 cm is low risk in cm 3 cm for history of witnessed apnoeas 43 – 47.9 cm is intermediate risk 4 cm for history of hypertension ≥ 48 cm is high risk

* Low risk equals a 17% probability of sleep apnoea. High risk equals 81% probability of sleep apnoea.

Table 4: OSA50 screening questionnaire for moderate to severe obstructive sleep apnoea19

Criteria If yes, SCORE

Obesity: Waist circumference* – Males >102cm or Females >88cm 3

Snoring: Has your snoring ever bothered other people? 3

Apnoeas: Has anyone noticed that you stop breathing during your sleep? 2

50: Are you aged 50 years or over? 2

TOTAL SCORE /10 points

If score = ≥ 5, proceed to overnight pulse oximetry

* Waist circumference to be measured at the level of the umbilicus

11 improving daytime symptoms. Treatment of OSAS is usually with continuous positive airway pressure (CPAP), which is Sleep studies often poorly tolerated by people without significant daytime sleepiness.12 Daytime sleepiness due to insufficient sleep Level I studies, referred to as polysomanography, are should be excluded prior to referral (see: “Consider the performed in a sleep laboratory with a technician presence of other sleep disorders”, Page 10). present and are the diagnostic gold standard. These studies include monitoring and recording of EEG Additional referral information that is likely to be required to (electroencephalography), EOG (electro-oculography), receive a publicly funded sleep assessment includes: EMG (electromyography), heart rate, blood oxygenation, Patient history, e.g. snoring, witnessed apnoeas nasal flow, thoracic and abdominal movement, limb Details of any previous otolaryngological assessments or movements and body position. procedures Co-morbidities, including cardiovascular, metabolic and Level II studies are unattended sleep studies recording psychiatric the same parameters as Level I studies. Social circumstances, including any current psychosocial Level III studies record airflow, respiratory effort, blood stressors oxygenation and heart rate. This level should be regarded Occupational risk, especially if sleepiness is threatening as the minimum standard when diagnosing patients with the patient’s employment obstructive sleep apnoea. Current medicines BMI and history of any recent weight change Level IV studies record two parameters, typically blood oxygenation and heart rate. Some level IV studies also record nasal flow. This level of sleep study should be used Private sleep clinics and/or home-based partial sleep studies with caution as oximetry only detects apnoea-hyponoea are an alternative to referral to specialist sleep laboratories episodes leading to oxygen desaturation and are not where there are significant service delays. In New Zealand sensitive enough to detect some instances of obstructive some private clinics are resourced by respiratory physicians. sleep apnoea, e.g. mild sleep apnoea. For this reason a However, considerable debate exists about the validity of negative result will usually require a higher level study if portable testing for the diagnosis of OSAS, compared with obstructed sleep apnoea continues to be suspected. testing in dedicated sleep clinics. The diagnostic value of private studies is dependent on the variables that are measured. The 2007 American Academy of Sleep Medicine guidelines recommend level III sleep studies (see “Sleep studies”) as a diagnostic minimum.20 It is important for clinicians referring to private services to be aware of the level of sleep study used. Interpretation of the results from home-based partial sleep studies should be undertaken with the full clinical context of the individual patient.

Suggested contraindications to unattended home diagnostic sleep studies include:18 Congestive heart failure Stroke Cor pulmonale Chronic obstructive pulmonary disease Hypoventilation Other serious medical disorders, e.g. seizures, psychosis, valvular heart disease, asthma, kidney or liver failure

12 BPJ Issue 48 Treatment for obstructive sleep apnoea Both forms of CPAP have been shown to effectively control OSAS. Patient preference and economic considerations often Lifestyle interventions are the simplest approach to reducing determine which form of CPAP is provided. OSAS severity and improving other health parameters. Studies have shown that weight loss in patients with mild, moderate Correct mask selection and treatment adherence are and severe OSAS results in improvements in OSAS symptoms.21 essential. Many patients find masks uncomfortable and may A weight loss programme and a healthy lifestyle alone may experience a sensation of claustrophobia. CPAP mask leakage provide clinical benefit for patients with mild OSAS. In patients can result in treatment failure. Patients should be encouraged with more severe OSAS, life style interventions should be used to persevere with treatment for at least four weeks, as in conjunction with CPAP or other interventions. treatment acceptance often improves over time. Patients should also be encouraged to use the device throughout their All patients with OSAS who smoke should be offered smoking sleep as increased treatment time is associated with increased cessation advice in the ABC format (Ask, Brief advice, Cessation benefit.24 Patients may report difficulties with adherence due support). to nasal dryness or bleeding, throat irritation, skin irritation, local sweating, pressure intolerance or a poor mask fit.12 It is Avoidance of medicines or drugs that may contribute to OSAS. essential that the operation of the device is understood, and There is no conclusive evidence that alcohol, benzodiazepines any issues that may affect adherence are addressed. CPAP or opioids exacerbate OSAS. However, in theory, these machines with built-in humidifiers and the use of silicon gels or substances could relax upper airway dilatory muscles, reduce plasters and facial shaving may alleviate some of these adverse ventilator drive or diminish the likelihood of arousing from effects. It has been reported that adherence to CPAP treatment an apnoea. If required, opioids and benzodiazepines should among Māori with OSAS may be less than adherence among be prescribed at the lowest effective dose. Alcohol should be New Zealand Europeans.25 avoided, especially in the few hours prior to bedtime.

Mandibular advancement devices Continuous positive airway pressure (CPAP) Mandibular advancement devices can prevent sleep apnoeas CPAP treatment is reported to be 100% effective at eliminating by widening the upper airway and pushing the pharyngeal fat obstructive sleep apnoea, if tolerated. It is recommended pads laterally and moving the tongue base muscles anteriorly. as first-line treatment for people with moderate or severe These may be a suitable treatment for patients with mild to OSAS.12 A meta-analysis of 23 randomised controlled trials moderate disease, or as a second-line treatment for patients found that CPAP significantly reduced daytime sleepiness in who cannot tolerate CPAP. There are many types of mandibular patients with moderate or severe OSAS.12 CPAP treatment in device available. Adverse effects, including teeth and jaw pain, people with OSAS has also been found to improve cognitive are likely to influence treatment adherence. A New Zealand function, reduce arterial blood pressure and reduce the rate study assessing the use of a mandibular advancement splint in of motor vehicle accidents by up to 83%.12, 22 Some studies 18 males and one female, with varying severities of obstructive have demonstrated improved glycaemic control in patients sleep apnoea, found that treatment resulted in significant following CPAP initiation.23 However, CPAP treatment is not improvements in the apnoea-hypopnoea index and other associated with weight loss.21 indices associated with OSAS, including snoring volume.26 However, the device was poorly tolerated with approximately Generally, CPAP treatment is not considered to be appropriate one-quarter of participants reporting that adverse effects for people with milder OSAS without significant symptoms, as prevented regular use of the device.26 In general, mandibular the inconvenience of the device is thought to outweigh the splints can only be fitted in patients with all or most of their benefits, resulting in poor adherence to treatment.12 own teeth.

CPAP prevents upper airway collapse by delivering positive A Cochrane review found that use of a mandibular advancement air pressure through a mask which is worn during sleep. There device improved subjective sleepiness and sleep disordered are two forms of CPAP; fixed CPAP delivers constant pressure breathing in people with OSAS, compared to control.27 Several throughout the night, and auto-titrating CPAP devices adjust studies have also reported significant decreases in blood the pressure delivery as the patient breathes. Auto-titrating pressure in the order of 2 – 3 mmHg following four to ten devices can be used to monitor treatment effectiveness and weeks of treatment with a mandibular advancement device.28 titrate CPAP pressure in patients commencing treatment.

BPJ Issue 48 13 Treatment with a mandibular advancement device appears to be more successful in people with milder forms of OSAS, Obstructive sleep apnoea and driving risk females, younger or leaner people, or people with supine- dependent sleep apnoea.28 People with OSAS can drive without restriction if their condition is well-managed with satisfactory control of Mandibular advancement devices can be purchased from symptoms.31 However, in some cases the New Zealand some community pharmacies and individually adjusted by a Transport Agency may impose licence conditions, with dentist, or custom-made by dentists or orthodontists. Custom- regular medical follow-up by the patient’s General fitted devices are often more effective and better tolerated Practitioner. than more generic devices. If the degree of advancement is too small then the device will not be effective, and if it is too People with OSAS should be advised not to drive if:31 large, adverse effects are increased. There is a high level of concern regarding sleepiness when driving while awaiting diagnosis from a sleep Tongue-retaining devices are designed to widen the upper study airway by pulling the tongue forward by suction. There is They have a history of sleep-related motor vehicle evidence that these devices may be as effective as mandibular accidents and report daytime sleepiness advancement devices if worn, however, they appear to be poorly tolerated by patients.29 They have a diagnosis of severe OSAS which is either untreated, or they are unwilling to accept treatment Pharmacological treatment of obstructive sleep apnoea The use of medicines for the treatment of obstructive sleep apnoea is controversial because they can mask diagnostically useful symptoms and reduce adherence to CPAP treatment.30 Modafinil, a respiratory stimulant, is licensed in New Zealand for the treatment of obstructive sleep apnoea, although it is only subsidised under Special Authority for the treatment of narcolepsy. Modafinil may be considered in limited circumstances only, and usually after consultation with a respiratory physician.

Surgical treatment of obstructive sleep apnoea Surgery may be appropriate for the treatment of OSAS in patients who have clear upper airway anatomical abnormalities, such as enlarged tonsils. Other patients are less likely to benefit from upper airway surgery, especially if obesity or other co- morbidities are present.

ACKNOWLEDGEMENT: Thank you to Dr Michael Hlavac, Respiratory and Sleep Physician, Canterbury Respiratory Services, Canterbury DHB for expert guidance in developing this article.

14 BPJ Issue 48 References 1. Paine S-J, Harris RB, Mihaere KM. Managing obstructive sleep apnoea Force of the American Academy of Sleep Medicine. J Clin Sleep Med and achieving equity: implications for health services. N Z Med J 2007;3(7):737–47. 2011;124(1334):97–104. 21. Bonsignore MR, McNicholas WT, Montserrat JM, Eckel J. Adipose tissue 2. Riha RL. Clinical assessment of the obstructive sleep apnoea/ in obesity and obstructive sleep apnoea. Eur Respir J 2012;39(3):746– hypopnoea syndrome. Ther Adv Respir Dis 2010;4(2):83–91. 67. 3. Hlavac M. Diagnosis and management of obstructive sleep apnoea. N 22. Giles TL, Lasserson TJ, Smith BH, White J, Wright J, Cates CJ. Continuous Z Fam Pract 2006;33(6):396–9. positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006;(3):CD001106. 4. Mihaere KM, Harris R, Gander PH, et al. Obstructive sleep apnoea in New Zealand adults: prevalence and risk factors among Māori and 23. Yang D, Liu Z, Yang H, Luo Q. Effects of continuous positive airway non-Māori. Sleep 2009;32(7):949–56. pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis. Sleep Breath 2012; [Epub 5. Lévy P, Tamisier R, Minville C, et al. Sleep apnoea syndrome in ahead of print] 2011: current concepts and future directions. Eur Respir Rev 2011;20(121):134–46. 24. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily 6. Schwartz AR, Patil SP, Laffan AM, et al. Obesity and obstructive sleep functioning. Sleep 2007;30(6):711–9. apnea: pathogenic mechanisms and therapeutic approaches. Proc Am Thorac Soc 2008;5(2):185–92. 25. Bakker JP, O’Keeffe KM, Neill AM, Campbell AJ. Ethnic disparities in CPAP adherence in New Zealand: effects of socioeconomic status, 7. Hensley M, Ray C. Sleep apnea. Am Fam Physician 2010;81(2):195. health literacy and self-efficacy. Sleep 2011;34(11):1595–603. 8. Rich J, Raviv A, Raviv N, Brietzke SE. All-cause mortality and obstructive 26. Neill A, Whyman R, Bannan S, et al. Mandibular advancement splint sleep apnea severity revisited. Otolaryngol Head Neck Surg improves indices of obstructive sleep apnoea and snoring but side 2012;147(3):583–7. effects are common. N Z Med J 2002;115(1156):289–92. 9. Marshall NS, Wong KKH, Liu PY, et al. Sleep apnea as an independent 27. Lim J, Lasserson TJ, Fleetham J, Wright J. Oral appliances for obstructive risk factor for all-cause mortality: the Busselton Health Study. Sleep sleep apnoea. Cochrane Database Syst Rev 2006;(1):CD004435. 2008;31(8):1079–85. 28. Marklund M, Verbraecken J, Randerath W. Non-CPAP therapies in 10. Baguet J-P, Barone-Rochette G, Tamisier R, et al. Mechanisms of cardiac obstructive sleep apnoea: mandibular advancement device therapy. dysfunction in obstructive sleep apnea. Nat Rev Cardiol 2012; [Epub Eur Respir J 2012;39(5):1241–7. ahead of print] 29. Deane SA, Cistulli PA, Ng AT, et al. Comparison of mandibular 11. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the advancement splint and tongue stabilizing device in obstructive sleep association between sleep-disordered breathing and hypertension. apnea: a randomized controlled trial. Sleep 2009;32(5):648–53. N Engl J Med 2000;342(19):1378–84. 30. Black J. Pro: modafinil has a role in management of sleep apnea. Am J 12. National Institute for Health and Clinical Excellence (NICE). Continuous Respir Crit Care Med 2003;167(2):105–6. positive airway pressure for the treatment of obstructive sleep apnoea/ hypopnoea syndrome. NHS; 2008. Available from: www.nice.org.uk 31. NZ Transport Agency. Medical aspects of fitness to drive: a guide for (Accessed Nov, 2012). medical practitioners. NZ Transport Agency; 2009. 13. Young T, Blustein J, Finn L, Palta M. Sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. Sleep 1997;20(8):608–13. 14. Yee B, Campbell A, Beasley R, Neill A. Sleep disorders: a potential role in New Zealand motor vehicle accidents. Intern Med J 2002;32(7):297– 304. 15. Sparks B, Bartle A, Beckert L. Assessment of snorers in primary care: straight path to treatment. N Z Med J 2002;115(1155):269–71. 16. Mackay S. Treatments for snoring. Aust Prescr 2011;(34):77–9. 17. Naughton MT. Assessment and management of the patient presenting with snoring. Aust Fam Physician 2002;31(11):985–8. 18. Skjodt NM. Approach to outpatient management of adult sleep apnea. Can Fam Physician 2008;54(10):1408–12. 19. Chai-Coetzer CL, Antic NA, Rowland LS, et al. A simplified model of screening questionnaire and home monitoring for obstructive sleep apnoea in primary care. Thorax 2011;66(3):213–9. 20. Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task

BPJ Issue 48 15 Sleep disturbances: MANAGING PARASOMNIAS in general practice

16 Parasomnias are a broad group of disorders movement (non-REM) and rapid eye movement (REM) sleep associated with unusual behaviour when and are grouped based on the stage of sleep in which they sleeping, and at sleep onset and waking. The occur (see“The architecture of sleep”). The most common non- distinct conditions that make up the spectrum REM parasomnias are bruxism (teeth grinding), somnambulism (sleep walking), confusional arousals and sleep terrors. These of parasomnias are classified predominantly generally occur in the first third of the night, when non-REM into rapid eye movement (REM) and non-REM sleep is deepest. The most common REM parasomnias are parasomnias, based on when they occur during nightmares, REM behaviour disorder and recurrent sleep sleep. Most people do not seek medical attention paralysis. for sleep disorders, and many parasomnias cease over time, but for those people who do present General principles for managing a to primary care, treatment options include parasomnia environmental, psychological, physiological and, in Management of parasomnias consists of identifying and severe cases, pharmacological management. resolving any underlying causes, providing reassurance and advice on optimal sleeping practices (sleep hygiene), and What are parasomnias? where necessary, modification of the sleeping environment. In severe cases, pharmacological treatment may be considered. A sleep disorder is defined as the medical dysfunction of an individual’s sleep pattern. Parasomnias are a sub-category Exclusion of underlying causes may include investigation of sleep disorder. They involve abnormal and unnatural of:3, 4 movements, behaviours, emotions, perceptions and dreams Use of medicines with CNS-related adverse effects, e.g. that occur while falling asleep, during sleep, between sleep sedative hypnotics, SSRIs, beta-blockers and tricyclic stages or upon waking. antidepressants Use of non-pharmacological drugs with CNS-related Most people experience a parasomnia during their lifetime. A adverse effects, e.g. caffeine, nicotine, alcohol, illicit drugs large Canadian study found that 88% of children manifested at Anxiety or stress least one parasomnia between age five months and six years.1 Depression or other mental illness The incidence of parasomnias begins to decline after age 25 years. Almost all adults who experience parasomnias report a Dementia or confusion in older people history of parasomnias during childhood.2 Other sleep disorders, e.g. restless leg syndrome, sleep apnoea, narcolepsy The term parasomnia refers to a large number of individual conditions, each with a different aetiology and epidemiology. Reassurance that parasomnias are common, usually without In general, parasomnias can occur during non-rapid eye any specific cause and generally resolve over time may be

BPJ Issue 48 17 helpful. Household members should be advised that during Get out of bed if sleep onset does not occur within 20 parasomnia episodes, the person should not be woken as this minutes, perform a relaxing activity such as listening to may increase disturbance or lead to violent behaviour.3 If they music or reading for a short time and then return to bed have left their bed, the person should be gently redirected back to bed without waking, or if there is a history of violence, Making the sleep environment safe may be necessary if the observed but left alone. parasomnia behaviour involves leaving the bed. For example, place locks on second story windows, remove furniture, Sleep hygiene is the term used to describe a set of structured including mats and electrical cords, from around the bed, practices and habits that can help to maximise the quality and secure dangerous items such as knives or matches and secure duration of sleep, and therefore minimise the occurrence of exits to prevent wandering. parasomnias. Sleep hygiene advice includes:5 Go to bed when sleepy, and get up at the same time Scheduled waking may help to reduce the incidence of each day episodes of non-REM parasomnias such as somnambulism Avoid daytime napping (except in young children), (sleep walking). The patient is gently and briefly woken 15 – 5, 6 especially after 2 pm 30 minutes prior to the normal episode time. The procedure is repeated nightly for up to one month, and then a trial Avoid excessive light exposure prior to bed, e.g. without waking is done to assess whether there is a continued computer screens, cell phones response. Ensure that sleep and sex are the only uses of the bed Get regular exercise, ideally mid to late afternoon Pharmacological treatment (Table 1) may be considered when Limit caffeine, alcohol and tobacco intake, particularly at parasomnias become frequent, cause extreme anxiety or there night is potential for harm to the person or household members. The Have a hot drink, e.g. milk, prior to bed use of medicines to treat parasomnias is complex and rarely Avoid doing school-work or work prior to bed evidence based.4 There are no medicines currently approved

Table 1: Pharmacological treatment options for parasomnias in adults

Medicine group Medicine and dose Comments

Benzodiazepines Clonazepam 1 mg daily, prior to sleeping, Clonazepam is the first-line choice as it has titrated up if required.4 the strongest evidence base and a well known risk profile; however, it may be no more effective than any other benzodiazepine.6, 7

Tricyclic antidepressants Amitriptyline or nortriptyline, 10 mg daily If benzodiazepines are not effective or not prior to sleeping, titrated up if required.4 tolerated, tricyclic antidepressants can be trialled.

Melatonin Melatonin 2 – 12 mg daily, several hours prior An alternative first-line treatment for REM to sleeping.7 parasomnias. Where patients have a risk of falls, melatonin should be used in preference to clonazepam. Patients should be started on 2 – 3 mg and titrated up if required.

Melatonin is not subsidised, therefore the cost should be discussed with the patient before prescribing. Melatonin is supplied under Section 29, therefore availability may vary, check with your local pharmacy.

18 BPJ Issue 48 for use for parasomnias in New Zealand. Medicine should Non-REM parasomnias only be prescribed after exclusion of reversible underlying causes and all non-pharmacological options have been Somnambulism trialled.6 Pharmacological treatment is rarely recommended Somnambulism (sleep walking) is a series of behaviours that for children with parasomnias, and at present, the evidence is occur during sleep, such as changes in body position, gesturing limited.5 Where pharmacological treatment is considered for with the hand, playing with the sheets, sitting up in bed or a child, it should be discussed first with a paediatrician, sleep resting on the knees. These behaviours usually culminate physician or psychiatrist. in the person leaving the bed and moving around with an altered state of consciousness and impaired judgment, while Psychotherapy, particularly relaxation and cognitive behaviour still sleeping. Behaviours are often complex, co-ordinated therapy, where available, may be useful for some people with and semi-purposeful, such as getting dressed or rearranging parasomnias.6 furniture. Rarer reports have described people driving, using firearms and performing physical assaults.3 Referral to a sleep physician is recommended if treatment is ineffective, the risk of harm is significant, the symptoms are During episodes of somnambulism the person may be atypical or the diagnosis is unclear. communicative, and is often receptive to commands.2 Episodes

The architecture of sleep

Sleep occurs in a complex cycle, which is essential for and wakefulness. Sleep duration is the total time in a 24 hour physiological regulation, function and overall health. An period that a person sleeps, and is divided into non-REM and individual’s sleep architecture, i.e. the structure and pattern of REM sleep stages (Figure 1). Non-REM sleep is further divided their sleep, can have a significant effect on their quality of life, into stages, with “deepest” sleep occurring in Stage Four. day-time function and health. Quality of sleep is dependent on sleep duration, along with The 24-hour sleep cycle is divided into three broad stages; non- time of sleep onset and length of time spent in each stage of rapid eye movement (non-REM), rapid eye movement (REM) sleep.

Brief Awakening Awake

REM Sleep

Stage 1

Stage 2

Stage 3

Stage 4

Midnight 1:30 am 3:00 am 5:00 am 6:30 am

Figure 1: Human sleep architecture, showing deep sleep (Stage 4) early in the night and multiple REM stages

BPJ Issue 48 19 may last for more than 30 minutes, and usually end with the Treatment: person returning to bed and resuming normal sleep. Identify and manage any underlying cause such as sleep apnoea, periodic limb movements in sleep or a mental illness. Somnambulism occurs in up to 17% of children,8 and between Provide advice on sleep hygiene. Rarely, pharmacological 1 – 4% of adults.6 There is evidence that a genetic component intervention with benzodiazepines or tricyclic antidepressants (HLA gene DQB1) may contribute in some cases.6 can be considered in adults.

Treatment: Confusional arousals which occur in children are not of clinical Identify and eliminate any underlying trigger, most commonly concern and generally do not require further investigation. stress, fatigue or febrile illness,9 and medicines that are known to cause sleep walking, e.g. zopiclone or antihistamines.10 Intervention includes advice on sleep hygiene and changes Sleep terrors to the sleep environment to make it safer. Consider a trial of Sleep or night terrors are one of the most extreme and scheduled waking (Page 18). upsetting forms of parasomnia. Sleep terrors are characterised by intense fear, motor agitation, vocalisation and high levels Where there is a risk of harm to the person or household of autonomic activity, e.g. profuse sweating, mydriasis, members, pharmacological intervention with benzodiazepines tachycardia and tachypnoea.2 Episodes generally last no more or tricyclic antidepressants may be considered in adults. than two to three minutes, and end with either spontaneous return to normal sleep or waking with no memory of the Confusional arousals incident.2 Confusional arousals are partial awakenings with impaired consciousness and memory, that can occur during deep sleep Sleep terrors occur in approximately 6.5% of children and <1% or upon attempted waking.11 Episodes typically last less than of adults, with no reported differences between genders.6 It five minutes, and in adults may be accompanied with unusual, is not known what causes sleep terrors but they are rarely violent or sexual behaviours and vocalisations.3 In adults, associated with any significant psychological illness.6, 13 confusional arousals may be an indication of depression or other mental illness.12 Treatment: Identify and manage any potential underlying triggers, e.g. Confusional arousals have a population prevalence of fatigue, stress, anxiety or febrile illness. Where a trigger cannot approximately 3%, with no reported differences between be identified provide reassurance and advice on good sleep genders.6 hygiene. A trial of scheduled waking may be useful.

Sleep talking partner. Febrile illness can increase the likelihood of sleep Sleep talking (somniloquy) is very common, particularly talking. Stress management and relaxation techniques in children. It can occur in both REM and non-REM phases prior to bedtime may be helpful to reduce sleep talking. of sleep. Vocalisations may be loud, and range from simple sounds to complex speeches. In most people At least some form of vocalisation is seen in most other sleep talking is benign and not associated with serious parasomnias, therefore it is important to distinguish psychopathology or any underlying issue.10 However, between simple sleep talking, and vocalisation sleep talking can be upsetting or disruptive for a bed accompanied by features of another parasomnia.

20 BPJ Issue 48 Bruxism Stranger than fiction: sleep sex and Bruxism (teeth grinding) is a common movement disorder midnight snacks in which a person grinds or clenches their teeth repetitively while asleep.12 Signs and symptoms include abnormal wear of Sleep sex (sexsomnia) is a rare variant of somnambulism the teeth, periodontal tissue damage and pain. in which a sleeping person engages in sexual activities while in non-REM sleep.15 Behaviours include vocalisation, Bruxism is most often reported in adults, with a prevalence of complex sexual activities and sexual violence.15 The approximately 20%, and no difference between genders.14 disorder is rare, and prevalence is unknown.

Bruxism occurs in 14% – 18% of children, although most infants Sleep-related eating disorder is a parasomnia, also exhibit some teeth grinding behaviours soon after incisor related to somnambulism, in which a sleeping person eruption.13 There is an increased prevalence of bruxism among involuntarily eats and drinks. Sleep eating behaviour is children with cerebral palsy and intellectual disabilities.12 more common that sleep sex, with a lifetime prevalence of approximately 5%.16 There is an increased prevalence Treatment: of sleep-related eating disorder among people who have Referral to a dentist is required where bruxism is causing an identified eating disorder, and it is often observed in significant wear to teeth.14 patients hospitalised for eating disorders.16 Women are more likely to report sleep eating than men. As stress may be a contributing factor, potential causes should be explored and eliminated where possible.13 Treatments for sleep eating and sleep sex are similar to other types of parasomnias; identify any underlying Provide advice on sleep hygiene. Occlusal splints or devices causes, provide advice on sleep hygiene and make the may be trialled, but evidence suggests that they only sleep environment safe. Due to the rarity of sleep sex, temporarily reduce bruxism, without addressing the cause or little is known about the effectiveness of pharmacological reducing long-term recurrence.14 Occlusal splints should not treatment. Patients who do not respond to non- be used by children. Physiotherapy can be useful for resulting pharmacological intervention should be referred to a jaw or muscle pain and fatigue. Jaw muscles can be stretched sleep physician or psychiatrist.6 People with a history of by opening the mouth wide, and repeating this movement ten inappropriate sleep behaviours can be advised not to times, twice daily.14 Generally, pharmacological management sleep with a partner, as the close proximity of another of bruxism is not indicated.14 person may induce an episode.3

REM parasomnias

Nightmares

Nightmares are the most common REM parasomnia. They are defined as recurrent episodes of awakening from sleep or naps with detailed recall of dreams involving distressing or life threatening events. There is no confusion on waking. There is often a significant impact on the person’s waking state, reduced daytime function and reluctance to return to sleep. Awakenings generally occur during the second half of the sleep period. Recurrent dreams are often associated with some underlying psychopathology such as post traumatic nightmares.

Diagnostic criteria and definitions differ in the literature and prevalence is difficult to quantify, but it is estimated that recurrent, problematic nightmares occur in 4 – 8% of people.17

BPJ Issue 48 21 Treatment: prevalence increasing with age.6 REM sleep behaviour disorder Treatment for recurrent nightmares usually involves cognitive is more common in people with Parkinson’s disease and Lewy behavioural therapies, including systematic desensitisation body dementia.19 In addition, people with idiopathic REM and relaxation techniques, and imagery rehearsal therapy.18 sleep behaviour disorder have a significantly increased risk of Referral to a psychologist may be required, particularly if developing Parkinson’s disease and Lewy body dementia.20 dreams are related to a real life traumatic event. Treatment: All patients with suspected REM behaviour disorder REM sleep behaviour disorder should ideally be referred for an overnight sleep study REM sleep behaviour disorder is the intermittent loss of REM- (polysomnography) in a sleep clinic.6 The priority for most sleep muscle atonia (i.e. protective muscle paralysis), which publically funded sleep clinics is investigating patients with results in acting out dreams. Common behaviours include sleep apnoea, therefore patients with suspected parasomnias punching, kicking, leaping and running from the bed during may have to be referred to a private sleep clinic. A detailed dream enactment. history should be taken to help exclude other diagnoses.

Episodes usually occur after at least 90 minutes of sleep, once Making the sleeping environment safe is important for people the person has entered REM sleep, and usually in the later one- with REM sleep behaviour disorder. As the risk of injury to the third of the night. They may be very frequent, occurring up to person and household members can be high, medicines are four times per night, on consecutive nights.12 usually considered, along with standard sleep hygiene advice. Clonazepam and melatonin are the most commonly used REM sleep behaviour disorder has a population prevalence medicines for REM sleep behaviour disorder (see Page 18 for of 0.5 – 2% and is most commonly seen in adult males, with recommended doses).

Table 2: The differentiation of parasomnias from nocturnal frontal lobe epilepsy22–24

Non-REM Parasomnia REM Parasomnia Frontal Lobe Seizures

Usual age at onset Childhood Older adults Any age, most often between age 9 – 20 years

Gender bias None More common in males May be more common in males

Occurrence during the night First third At least 90 minutes after Most frequently between sleep onset 2 am and waking

Episodes per night Usually one One to several Several

Episode duration 1-30 minutes 1-2 minutes Seconds to one minute

Episode frequency Sporadic Sporadic Almost nightly

Episode amnesia Often total Occasionally total No amnesia

Stereotyped movement Absent Absent Present

Autonomic activity Present Absent Present

Evolution Tend to disappear Rare remission May increase in frequency

22 BPJ Issue 48 Recurrent sleep paralysis

Sleep paralysis is a common condition where complete muscle atonia (i.e. paralysis) accompanied by feelings of intense fear is Narcolepsy experienced in a conscious person (i.e. awake, not dreaming), Narcolepsy is a sleep disorder characterised by excessive at the transition from wakefulness to REM sleep or during sleepiness and daytime sleep attacks. The cause of waking from REM sleep. narcolepsy is unknown but it has been linked to reduced amounts of orexin, a protein in the brain (also know as Recurrent sleep paralysis has a life-time prevalence of hypocretin), and may be autoimmune or genetic (familial) approximately 10 – 20%, with as many as 50% of people in origin.21 experiencing an episode of sleep paralysis at least once.6 It is approximately twice as common in females as in males.6 It Symptoms usually first occur between age 15 – 30 years, is associated with several risk factors, including narcolepsy, and include:21 migraine, anxiety, obstructive sleep apnoea and exhaustion. Periods of extreme drowsiness during the day, with a strong urge to sleep, often followed by a short “sleep Treatment: attack” (lasting approximately 15 minutes) If episodes are frequent, ask about any history which may Visual and auditory hallucinations between sleep suggest signs of narcolepsy (see “Narcolepsy”). Assess for any and wakefulness other underlying cause such as migraine, anxiety, exhaustion Sleep paralysis or sleep apnoea. If no underlying cause is found, provide Cataplexy (sudden loss of muscle tone), which can advice on good sleep hygiene and reassurance that the be triggered by strong emotions, e.g. laughter or condition is not harmful and will cease with time.6 If episodes anger, usually lasting for less than 30 seconds, but are persistent, severe or causing or worsening anxiety, the use in severe cases, paralysis may last for up to several of tricyclic antidepressants at bed-time may be beneficial (see minutes Page 18 for recommended doses).

A patient with suspected narcolepsy should be referred to A diagnosis not to be missed: differentiating a sleep specialist for further assessment, including a sleep parasomnias from nocturnal frontal lobe study (polysomnography). epilepsy In some people, the signs and symptoms of nocturnal frontal lobe epilepsy may mimic that of a parasomnia, therefore it is essential not to miss this diagnosis. Table 2 lists features that may help differentiate between non-REM and REM parasomnias and frontal lobe seizure.

Frontal lobe epilepsy usually begins between age 9 – 20 years.22 Episodes are characterised by repetitive behaviours of short duration (often less than 30 seconds) and asymmetric, abnormal body movements, such as dystonic and dyskinetic postures.23 Grimacing and vocalisation may be present.22 Tongue biting and urinary incontinence are rare, but their presence significantly increases the likelihood of a diagnosis of nocturnal seizures rather than a parasomnia.24

Parasomnias, in contrast, appear from an earlier age in children, and in adults are usually preceded by a history of childhood parasomnias. Parasomnic episodes have a longer duration and, with the exception of REM behaviour disorder, rarely have same-night recurrence, and have a decreasing frequency or cessation after puberty for most people.

BPJ Issue 48 23 Sleep starts (hypnic jerks): weirdly ACKNOWLEDGEMENT: Thank you to Dr Alex Bartle, normal Sleep Physician, Director Sleep Well Clinics, New Zealand for expert guidance in developing this Some sleep disturbances and symptoms are a normal article. part of sleep. Hypnic jerks, commonly known as sleep starts, are non-periodic myoclonic movements, usually involving the lower limbs, which occur at sleep onset or waking. They may be described by patients as jerking or jolting movements or the sensation of falling just as they are about to fall asleep, often accompanied by a feeling of fright and brief tachycardia.12

Hypnic jerks are reported to affect 70% of adults, and are considered a normal part of sleep.6 There is usually no particular cause, although they have been linked to fatigue, stress, sleep deprivation, vigorous exercise and some stimulants, such as caffeine.

References 1. Petit D, Touchette E, Tremblay R, et al. Dyssomnias and parasomnias in 13. Mindell J, Owens J. A clinical guide to pediatric sleep. 2nd ed. early childhood. Pediatrics 2007;119(5):1016–25. Philadelphia, USA: Lippincott Williams & Wilkins; 2003. 2. Provini F, Tinuper P, Bisulli F, et al. Arousal disorders. Sleep Med 2011;12, 14. BMJ Best Practice. Bruxism. BMJ;2011. Available from: http:// Supplement 2:S22–S26. bestpractice.bmj.com (Accessed Nov, 2012). 3. Howell MJ, Schenck CH. Chapter 44 – NREM Sleep Parasomnias in 15. Andersen ML, Poyares D, Alves RSC, et al. Sexsomnia: Abnormal sexual Adults: Confusional Arousals, Sleepwalking, Sleep Terrors, and Sleep- behavior during sleep. Brain Research Rev. 2007;56(2):271–82. Related Eating Disorder. Therapy in Sleep Medicine. Philadelphia: W.B. 16. Brion A, Flamand M, Oudiette D, et al. Sleep-related eating disorder Saunders; 2012. p. 559–72. versus sleepwalking: A controlled study. Sleep Med 2012;13(8):1094– 4. Wilson S, Nutt D, Argyropoulos S, et al. British Association for 101. Psychopharmacology consensus statement on evidence-based 17. Spoormaker VI, Schredl M, Bout J van den. Nightmares: from anxiety treatment of insomnia, parasomnias, and circadian rhythm disorders. symptom to sleep disorder. Sleep Med Rev 2006;10(1):19–31. J Psychopharm 2010;24(11):1577–600. 18. Krakow B, Kellner R, Pathak D, et al. Imagery rehearsal treatment for 5. BMJ Best Practice. Parasomnias in children. BMJ; 2012. Available from: chronic nightmares. Behav Res Ther 1995;33:837–43. http://bestpractice.bmj.com (Accessed Nov, 2012). 19. Boeve BF, Silber MH, Ferman TJ. REM sleep behavior disorder in 6. BMJ Best Practice. Parasomnias in adults. BMJ; 2012. Available from: Parkinson’s disease and dementia with Lewy Bodies. J Geriatr Psych http://bestpractice.bmj.com (Accessed Nov, 2012). Neur 2004;17(3):146–57. 7. Aurora R, Zak R, Maganti R, et al. Best Practice Guide for the treatment 20. Postuma R, Gagnon J, Vendette M, et al. Quantifying the risk of of REM sleep behaviour disorder. J Clin Sleep Med 2010;6(1):85–95. neurodegenerative disease in idiopathic REM sleep behavior disorder. 8. Agargun M, Cilli A, Sener S, et al. The prevalence of parasomnias Neurology 2009;72:1296–300. in preadolescent school-aged children: a Turkish sample. Sleep 21. Morrison I, Riha RL. Excessive daytime sleepiness and narcolepsy 2004;27:701–5. — An approach to investigation and management. Europ J Int Med 9. Pressman MR. Factors that predispose, prime and precipitate NREM 2012;23(2):110–7. parasomnias in adults: Clinical and forensic implications. Sleep Med 22. Haut S, Benbadis S. Frontal Lobe Epilepsy. Medscape Reference; 2012. Rev 2007;11(1):5–30. Available from: http://emedicine.medscape.com/article/114076- 10. Kryger M, Roth T, Dement M. Principles and practice of sleep medicine. overview/ (Accessed Nov, 2012). 5th ed. Connecticut, USA: Elsevier Health Sciences; 2010. 23. Benbadis S. The differential diagnosis of epilepsy: A critical review. 11. Pelayo R, Yuen K. Pediatric Sleep Pharmacology. Child and Adolescent Epilepsy Behavior 2009;15(1):15–21. Psychiatric Clinics of North America 2012;21(4):861–83. 24. Tinuper P, Provini F, Bisulli F, et al. Movement disorders in sleep: 12. American Academy of Sleep Medicine. The international classification Guidelines for differentiating epileptic from non-epileptic of sleep disorders, revised. AASM, USA; 2001. Available from: www. motor phenomena arising from sleep. Sleep Medicine Reviews aasmnet.org (Accessed Nov, 2012). 2007;11(4):255–67.

24 BPJ Issue 48 Update on azithromycin new prescriber information and availability

What are the changes? The recommended indications for 1. Azithromycin granules for oral liquid (40 mg/mL and 200 azithromycin remain the same mg/5mL are now fully subsidised, with no requirement Recommended first-line indications for azithromycin are: for endorsement of the prescription (from 1 November, 2012). Chlamydia infections – Adults: 1 g stat 2. As of 1 December, 2012, a 250 mg azithromycin tablet will be available, fully subsidised, in addition to the Infants born to mothers who have chlamydia are at increased risk current 500 mg tablet. This is because the 500 mg tablet of pneumonia and conjunctivitis. Treatment with azithromycin is unscored and doses may be inaccurate if the tablets suspension is appropriate if the infant has laboratory proven are broken. neonatal chlamydia conjunctivitis or pneumonia. The dose 3. A restriction on the length of time azithromycin is able should be discussed with a paediatrician. to be prescribed will now apply for all formulations. Azithromycin will be able to be prescribed for a Acute non-specific urethritis – Adults: 1 g stat maximum of five days and for longer periods only if specific endorsement criteria apply (see below). Pertussis (treatment and prophylaxis) – Children: 10 mg/kg on day one, followed by 5mg/kg/day for days two to five (five days total treatment). For children weighing >45 kg, dose as Some restrictions on funding are still in place per adults. Erythromycin is an alternative to azithromycin in The following funding restriction will apply to all community children aged over one year. dispensings of azithromycin 250 and 500 mg tablets: A maximum of five days treatment per prescription; Erythromycin is also the current recommended treatment which can be waived by endorsement for patients who and prophylaxis for pertussis in adults. Azithromycin is an have: alternative: 500 mg on day one, followed by 250 mg on days – Received a lung transplant and require treatment or two to five. prophylaxis for bronchiolitis obliterans syndrome*; or N.B. Previous guidance has given a different dosing regimen – Cystic fibrosis and chronic infection with for azithromycin in children for pertussis, depending on age Pseudomonas aeruginosa or Pseudomonas-related (under or over age six months). United States, United Kingdom gram-negative organisms* and Australian guidelines differ in their advice. The consensus A maximum of eight 500 mg tablets will continue to be in New Zealand is now to use the same regimen in children, available on PSO regardless of age. * Currently unapproved indications

BPJ Issue 48 25 Recommended second-line indications for azithromycin Long-term prophylaxis in patients with COPD include: There is increasing evidence that the long-term use of Pelvic inflammatory disease, as an alternative to azithromycin may decrease the frequency of exacerbations in doxycycline, when chlamydia is present – 1 g stat, people with COPD and improve their quality of life. However, repeated in seven days + ceftriaxone 500 mg IM stat + concerns about adverse effects and antibiotic resistance, mean metronidazole 400 mg, twice daily, for two weeks that routine use is not recommended. In a recent study of the use of azithromycin in people with COPD, approximately 5% of participants experienced a reduction in hearing after use Ensuring appropriate use of azithromycin of azithromycin, which was not always reversed on cessation.2 PHARMAC’s proposal to remove the prescribing restrictions Significant concerns were also raised regarding resistance on azithromycin was initially outlined in July 2012. Feedback to macrolides. The authors acknowledge that there was an on this proposal, however, raised concerns that the removal increase in the incidence of colonisation with macrolide– of all restrictions would result in inappropriate prescribing resistant organisms but that the significance of this for the of azithromycin. In particular, there were concerns that the patient, their families and the community is unknown.2 medicine would be used for its anti-inflammatory properties, that it would be used for the treatment of conditions for which Antibiotic resistance other antibiotics are effective and more appropriate, or as a Widened access and increasing use of azithromycin in other long-term prophylactic in chronic obstructive pulmonary countries have contributed to an increasing incidence of disease (COPD). It was thought that the widened access to macrolide-resistant organisms.3 Concerns have been raised azithromycin would increase the prevalence of azithromycin- that a similar situation will arise in New Zealand. It is therefore resistant micro-organisms in New Zealand. There were also important that azithromycin is only prescribed for the clinical questions raised about the safety of the use of azithromycin situations it is indicated for. ESR will be monitoring resistance due to recent evidence linking azithromycin with an increase data in New Zealand. in cardiovascular mortality.1 Azithromycin may be linked to an increased risk of In response to this feedback, PHARMAC altered the proposal cardiovascular death allowing azithromycin to be funded without restriction and A large retrospective cohort study found that a five day re-issued it with the restrictions as outlined. course of azithromycin was associated with a small increase in the risk of cardiovascular death when compared to the risk in patients who took no antibiotics or other antibiotics, e.g. Prescribing notes for azithromycin amoxicillin.1 Macrolide antibiotics, particularly erythromycin Appropriateness of the indication and clarithromycin have been associated with prolongation The recommended indications for the use of azithromycin of the QT interval and there is increasing evidence that remain the same. Azithromycin is not recommended for use azithromycin may also be proarrhythmic.4 Although there has in the majority of patients with upper or lower respiratory been criticism of the study and further research is required, tract infections such as otitis media, sore throat or community the authors conclude that the key factors that need to be -acquired pneumonia. considered when prescribing azithromycin are the patient's baseline cardiovascular risk and the appropriateness of the Anti-inflammatory properties in long-term conditions indication for which azithromycin is prescribed.1, 4 Macrolide antibiotics, such as azithromycin, have immunomodulatory and anti-inflammatory effects in For more information on the changes to azithromycin, see: addition to their antimicrobial activity and in patients with “Approval of proposal to amend the restrictions applying to some conditions, e.g. cystic fibrosis, this can be beneficial. azithromycin and list Apotex’s brand of azithromycin 250 mg Azithromycin has been subsidised since 1 July, 2009 for use in tablets”, PHARMAC, Oct 2012; Available from www.pharmac. patients with cystic fibrosis and chronic infection. There may govt.nz/2012/10/19/AzithromycinNotification.pdf be a role for azithromycin in patients with non-cystic fibrosis bronchiectasis. The evidence for this is currently under review For more information on the use of azithromycin, see: and the indication will be widened if appropriate. “The appropriate use of macrolides”, BPJ 44 (May, 2012).

26 BPJ Issue 48 ACKNOWLEDGEMENT: Thank you to Dr Emma Best, Paediatric Infectious Diseases Consultant, Starship Children’s Health, Auckland and Dr Simon Briggs, Clinical Director, Infectious Diseases Service, Auckland City Hospital, Auckland for expert guidance in developing this article.

References 1. Ray WA, Murray KT, Hall K et al. Azithromycin and the risk of COMING SOON cardiovascular death. NEJM 2012;366(20):1881-90.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. NEJM 2011;365(8):689-98. Prescribing 3. Jenkins S, Farrell D. Increase in pneumococcus macrolide resistance, United States. Emerg Infect Dis 2009;15. antipsychotics 4. Ray WA, Murray KT, Stein CM. Authors reply. NEJM 2012;367(8):775. to older people: a special edition clinical audit

www.bpac.org.nz

27 When and how to use a syringe driver in palliative care

28 Syringe drivers are often required to provide medicines for symptom management in patients The Niki T34 is used in a community who are terminally ill. They allow continuous setting subcutaneous administration of medicines to The lockable, battery operated, Niki T34 syringe driver enable effective symptom control when medicines is the current device available in New Zealand for the given by other routes are inappropriate or no longer continuous subcutaneous administration of medicines effective. With guidance and support from the in a community setting. The Graseby syringe driver local hospice or district nursing services, General has been gradually phased out of use as it was not Practitioners can arrange a syringe driver infusion tamper-proof. Concerns were also raised by the Health for a patient in their home or in a residential care and Disability Commissioner after a number of cases 1 facility, prescribe and monitor the appropriate mix occurred due to errors with syringe driver use. As a result, a recommendation was made that there be consistency of medicines and manage breakthrough symptoms. in the type of syringe driver used throughout New Zealand. Initially the preferred replacement option was What is a syringe driver? the AD Ambulatory Syringe Driver, however, the company involved was unable to supply and support these drivers A syringe driver is a small, portable, battery operated device and a further decision was made so that by 30 June, 2011, that administers medicines subcutaneously over a selected the Niki T34 syringe driver was used exclusively.2 time period, usually 24 hours. Medicines are drawn up into a syringe that is then attached to the driver, which is set to move the plunger of the syringe forward at an accurately controlled rate. Syringe drivers can be used either short-term or long-term, for patients who are ambulatory and those who are confined to bed. Syringe drivers can be placed into a carry bag or pouch when a patient is mobile or be tucked under a pillow if the patient is bed-bound.

Indications for use of a syringe driver Continuous subcutaneous administration of medicines using a syringe driver often becomes necessary for the control of symptoms during palliative care. A syringe driver is useful when the oral route of administration is not possible and repeated subcutaneous doses are inappropriate, ineffective or impractical. Although medicines can also be administered by other routes, such as rectal or sublingual, a further advantage of a continuous subcutaneous infusion is that any peaks and troughs of intermittent delivery methods are avoided (Table 1)

BPJ Issue 48 29 Table 1: Advantages and disadvantages of using a syringe driver4–6

Advantages Disadvantages

The ability to gain effective symptom control due to Medicine requirements must be anticipated for a 24 steady plasma drug concentrations without peaks and hour period and can result in a loss of flexibility in troughs dosing Allows management of multiple symptoms through the Medicines given by other routes (including “as needed” use of combinations of medicines given via a single route subcutaneous injections) may be required to manage The single route of administration minimises the need for the patients symptoms for the initial four hours of the repeated injections or multiple oral medicines syringe driver infusion while the medicines reach a Subcutaneous administration of medicines is more plasma concentration that provides effective symptom comfortable for the patient than intramuscular injections control (particularly if the patient is cachexic) and is simpler and An increase in the patients symptoms may require less invasive than medicines given intravenously additional injections for relief The ability for patients who are still mobile to remain so, Local reactions such as pain, inflammation or infection and once set up enables more independence can cause discomfort and interfere with the delivery and absorption of the medicines Patients may see the use of a syringe driver as a final step before death and find its use disconcerting and obtrusive The patients symptoms and effectiveness of the infusion must still be reassessed regularly

Consider using a syringe driver when:3 to be discussed with the patient and family and any concerns The patient is unable to take medicines by mouth due addressed. A syringe driver simply provides an alternative to nausea and vomiting, severe oral lesions, e.g. mucosal route for the administration of medicines. For example, a ulceration, dysphagia, weakness, sedation or coma patient with severe nausea and vomiting that temporarily prevents the use of oral medicines may need a syringe driver There is poor absorption of oral medicines to gain control of symptoms. It may be possible to revert back Pain is not able to be controlled using orally administered to the use of oral medicines once control of the nausea and medicines vomiting is achieved.4 There is a malignant bowel obstruction and further surgery is inappropriate (therefore avoiding the need for Topics of discussion with the patient and family/whānau may an intravenous infusion or the insertion of a nasogastric include: tube) Any past experience they have had with syringe drivers The patient does not wish to take regular medicine by The stage of illness they are at and what using a syringe mouth driver means for them for the future, e.g. prognosis Reassurance that syringe drivers do not always mean that death is imminent Talking about syringe drivers with patients and family/whānau Explanation that a syringe driver allows the symptoms associated with the process of dying to be managed, but does not speed up the process of dying Initiating use of a syringe driver in a patient during palliative care may represent a significant and unwelcome milestone for Addressing any fears or anxieties about the syringe driver, the patient and their family/whānau, because syringe drivers including the medicines used, e.g. opioids are often required when a patient is close to death. The goals Advance care planning options and specific advance care of administering medicines via a syringe driver therefore need directives

30 BPJ Issue 48 Practical aspects of how the syringe driver functions also need given in doses not seen in routine day-to-day practice.5 to be discussed with the patient and their family/whānau. In Most medicines can be used in a subcutaneous infusion, many cases, it will be the family who become aware of any however, chlorpromazine, prochlorperazine and diazepam issues with the device itself or that the medicines are not are contraindicated as they can cause skin reactions at the controlling the patient’s symptoms. injection site.

Some of the practical issues that may need to be addressed Infusions for administration via continuous subcutaneous include: infusion using a syringe driver should be prescribed to run Care of the syringe driver once in use over 24 hours, although medicines mixed together may be The safety aspects of the syringe driver pharmaceutically compatible and stable for longer than this. What to do and where to get advice if the syringe driver The patient should ideally be reviewed every day so that is not working properly, or symptoms are not controlled, medicine doses can be adjusted according to their needs. e.g. who to call if an alarm sounds, ensuring that a spare battery is available When prescribing consider: Ways to carry the infusion device to minimise its The patient’s medicine requirements for 24 hours intrusion in daily life, e.g. while showering The doses that may be required for breakthrough The potential need to administer additional medicine symptoms – these need to be available for immediate via other routes, e.g. at initiation, for breakthrough use symptoms The choice of diluent Arranging a syringe driver for a patient The compatibility of the medicines required to manage symptoms (Table 2, over page). In general, avoid Hospice or district nursing services can provide equipment combining more than three medicines in one syringe and certified staff who can work with General Practitioners, (occasionally more than one syringe driver is required) patients and their families/whānau. Many patients will also be under the care of a palliative care physician. It is essential that there is good communication between the people who Choice of diluent are providing care and support for the patient and their family The choice of diluent for the infusion solution varies according (this also includes community pharmacy). Many residential to local guidelines as there is evidence for and against the aged care facilities have syringe drivers on site and staff trained two most commonly used diluents – sterile water (water for in their use. injection) and normal saline (NaCl 0.9%).3 In general, sterile water is used. Hospice New Zealand offers a training programme on managing syringe drivers in primary care. For further Sterile water is compatible with most medicines (with information see: www.hospice.org.nz some exceptions, e.g. levomepromazine, ondansetron and octreotide which should be diluted with normal saline) and unlikely to cause precipitation of medicines, but it is hypotonic Most symptoms can be controlled with a continuous and may be associated with pain at the infusion site.3,7 However, subcutaneous infusion in practice, pain is not that common because of the slow rate In a palliative care setting, subcutaneous administration of of infusion. medicines given via a syringe driver is useful for managing symptoms such as pain, nausea, anxiety and restlessness. Normal saline is also compatible with most medicines (with Injectable forms of medicines to control symptoms can be some exceptions, e.g. cyclizine which should be diluted with given alone, or mixed together in a syringe depending on sterile water) and may be less irritating at the insertion site their physical and chemical compatibility and the diluents because it is isotonic, however, the likelihood of precipitation used (over page). increases, particularly when more than one medicine is used.

Compatibility of medicines Choice of medicine and prescribing When more than one medicine is used in an infusion solution In palliative care, medicines may be prescribed for unapproved there is a risk that they may not be compatible, either chemically indications, be administered by an unapproved route or or physically. Increasing the number of medicines in the

BPJ Issue 48 31 Table 2. Compatibility of medicines for syringe driver infusions commonly prescribed in general practice (Adapted from Palliative Care Handbook 2012).7

Medicine Morphine Oxycodone Fentanyl Methadone Metoclopramide Cyclizine Haloperidol Methotrimeprazine Midazolam Clonazepam butylromide Hyoscine Dexamethasone

Morphine – NA NA NA Y Y Y/SI Y Y Y Y/? Y

Oxycodone NA – NA NA Y SI Y Y Y Y Y Y

Fentanyl NA NA – NA Y SI Y Y Y ? Y ?

Methadone NA NA NA – Y ? Y Y Y Y ? Y

Metoclopramide Y Y Y Y – Y Y Y Y Y Y Y

Cyclizine† Y SI SI ? Y – Y Y SI SI SI SI

Haloperidol Y/SI Y Y Y Y Y – Y Y Y Y SI

Levomepromazine Y Y Y Y Y Y Y – Y Y Y SI (Methotrimeprazine)

Midazolam Y Y Y Y Y SI Y Y – Y Y SI

Clonazepam Y Y ? Y Y SI Y Y Y – Y Y

Hyoscine butylbromide Y/? Y Y ? Y SI Y Y Y Y – Y (Buscopan)

Dexamethasone‡ Y Y ? Y Y SI SI SI SI Y Y –

=Compatible =Sometimes incompatible (usually at higher doses) =Not usually used together =unknown Y SI NA ?

† May crystallize, dilute well ‡ 0.5 to 1mg dexamethasone added to a syringe driver solution may reduce the risk of irritation at the subcutaneous insertion site

If more than two medicines are to be mixed in an infusion, refer to The Palliative Care Handbook 2012 or contact your local hospice for commonly used combinations and additional compatibility information

32 BPJ Issue 48 solution increases the risk of problems with the combinations. the total daily dose, e.g. metoclopramide, oxycodone and Physical incompatibility usually results in changes in the fentanyl, or medicines that are potentially irritant when given solution that can be observed such as discolouration, clouding subcutaneously, e.g. cyclizine, methadone and high doses of or precipitation of crystals or particles. However, it is important dexamethasone. to refer to compatibility tables because a solution can remain clear even if the medicines are chemically incompatible. The first syringe of a new prescription will lose some of the solution when the line is primed, therefore the infusion will Precipitation may occur as a result of a reaction between not run for a full 24 hours. An initial subcutaneous injection medicines in a syringe. The risk of precipitation can be may also be required as a loading dose to manage the patient’s minimised by using sterile water as the diluent and by symptoms for the initial two to four hours of syringe driver maximising the total volume of the solution in the syringe, i.e. use until the medicines in the infusion reach effective blood making the solution as dilute as possible.7 plasma levels. When an infusion is due to be changed, a delay of an hour or two should not cause problems if the patient’s Once mixed, syringes should be observed for any signs of symptoms are well controlled. This can be a concern for precipitation or discolouration. Provided that doses are within patients and families if the clinicians or nurses visit is delayed. normal ranges, Table 2 shows which injectable medicines are expected to be compatible in a 24-hour syringe driver Hospices and residential aged care facilities are likely to have solution. standardised prescribing and administration charts for syringe driver prescriptions. Similar documentation is recommended Prescribing the medicines for the syringe driver for patients who are receiving care at home. Convert the patient’s previous 24-hour oral medicine requirements (including regular and “as needed” doses) to the An example of a prescription chart for documenting equivalent subcutaneous dose. medicines given via syringe driver is available at: http://palcare.streamliners.co.nz click on “forms”. Usual starting doses for subcutaneous infusion for commonly used medicines are: The individual medicines to go in the syringe can be prescribed Morphine – use half the total 24 hour oral dose on a standard prescription for a community pharmacy. Oxycodone – use half the total 24 hour oral dose Indicate the prescription is for a syringe driver. State the dose and diluents, and remember a triplicate controlled drug Metoclopramide, cyclizine and hyoscine hydrobromide prescription for any opioids. Some community pharmacies (the injectable hyoscine salt Buscopan) – same as the oral provide a service for compounding medicine solutions in daily dose subcutaneous syringes. Haloperidol – antiemetic dose is 1 – 2 mg for 24 hours

Midazolam – 5 – 40 mg over 24 hours Administration instructions do not need to include the rate of infusion, just the infusion duration (usually 24 hours). This is For patients who have not been on opioid medicine for because the Niki T34 syringe driver simplifies administration analgesia, an example of an initial starting dose would be 10 by detecting the syringe size and volume of medicine, and sets mg morphine subcutaneously over 24 hours.3 the rate to deliver the infusion over the required time period, e.g. 18 mL in a 20 mL syringe will deliver at 0.75 mL per hour Prescribe the doses of the subcutaneous medicines to cover for a 24-hour period. a 24-hour period. Check the compatibilities of the medicines in the syringe using the chart in The Palliative Care Handbook Controlled drugs that are no longer required for a patient 2012 or Table 2 and decide on the volume to infuse, stating the can be returned to the pharmacy or general practice for safe diluents. A maximum of 24 mL solution in a 30 mL syringe is disposal. appropriate for the Niki T34 syringe pump. Smaller syringes, e.g. 10 mL and 20 mL, can also be used, but they should be filled to a maximum of 8 mL and 18 mL respectively. A luer-lock syringe Starting the infusion should always be used to avoid any risk of disconnection. In most cases, a healthcare professional trained in the use of syringe drivers, e.g. a hospice nurse, district nurse or Larger volume syringes should be used for medicines that residential aged care facility nurse, will assist with setting up will require more ampoules to be combined to achieve the continuous subcutaneous infusion.

BPJ Issue 48 33 A step by step guide for operating the Niki T34 is available a site when it becomes necessary, e.g. due to pain, swelling or from the manufacturer, REM Systems. Instructions are also inflammation.3, 4 available online from many hospices. Techniques that may help to prolong the usefulness of a site Selection of the infusion site and to minimise reactions include: Plastic cannulae are recommended, although metal butterfly Make the solution as dilute as possible – use a larger needles can be used. The preferred sites for insertion of the syringe cannula for a continuous subcutaneous infusion are: When possible, select a solution that is close to The anterior chest wall physiological tonicity – sterile water is hypotonic, normal The anterior abdominal wall saline is isotonic, and solutions with high concentrations of some medicines become hypertonic The anterior aspect of the upper arms Use plastic cannulae as they cause less site irritation than The anterior aspect of the thighs metal cannulae In a patient who has been prone to site problems, These sites are preferred because they are accessible, both consider rotation of the site of infusion before any for initial insertion and for monitoring, and they are rarely localised reactions develop oedematous.3 The choice of site may be influenced by a number of factors including patient preference, their level of Avoid oedematous areas when selecting the site for mobility and the patient’s condition, e.g. if they are cachexic infusion the abdomen may be the most suitable site, the upper arm Use 0.5 – 1 mg of dexamethasone in the syringe driver should be avoided if the patient is bed-bound and requires solution to reduce site reactions, particularly if the regular turning and anterior sites may not be suitable for medicines used are known to be irritant, e.g. methadone6 patients who are agitated as they may dislodge the cannula Consider the use of heparinoid (Hirudoid) cream (not – a posterior site over the scapula may be preferable. subsidised) on inflamed sites if there is no infection present6 Inappropriate sites include:3,5 Lymphoedematous or ascitic areas – as absorption will Monitoring the infusion be reduced and there is an increased risk of infection and Patients being cared for at home should ideally have a daily leakage visit from a health professional for review of symptom control and monitoring of the infusion. This should occur at least every Areas of skin that are scarred, broken, inflamed, infected four hours when patients are in a hospice or residential aged or hairy care facility. Skin folds or skin over bony prominences or near joints The anterior chest wall in patients who are very cachexic A check should be made of the: – there is a small risk of pneumothorax Cannula site – for redness, swelling, leakage or cannula The upper abdomen in a patient with an enlarged liver – blockage or displacement there is a small risk of puncturing the liver capsule Tubing – for kinks or knots in the tubing Skin that has been irradiated within the last six weeks Syringe – for precipitation or crystallisation, discolouration of solution Any area that has a tumour Syringe driver – to ensure that the syringe remains in the correct position, that the infusion is running at the Minimising reactions at the site of insertion correct rate and the syringe driver battery has enough A number of factors influence the longevity of the insertion power to last until the next check site. These include the site selected, the type of cannulae used and the medicine being given. If problems arise with an infusion site the patient may have localised discomfort, or Managing breakthrough symptoms there may be reduced absorption of the medicine and a loss First check that the medicines are being delivered effectively of symptom control. As a general guide, plastic cannulae can via the syringe driver. stay in place for up to a week or more, whereas metal cannulae remain viable for approximately 72 hours.3, 6 Provided there is Breakthrough pain can be treated with additional subcutaneous no evidence of a site reaction, it is reasonable to only change doses of the opioid being used (usually morphine). If possible,

34 BPJ Issue 48 doses should be given through a side port in the syringe driver References cannula line to minimise patient distress. This can be given as 1. Health and Disability Commissioner (HDC). Decision 05HDC05278. often as required to relieve breakthrough pain. Doses can be HDC; 2005. Available from: www.hdc.org.nz/decisions--case- notes/commissioner’s-decisions/2005/05hdc05278 (Accessed prescribed in a flexible manner to achieve good symptom Nov, 2012). control, e.g. 2.5 mg morphine as required every 15 minutes up 2. Health Benefits Limited (HBL). Syringe driver update. HBL; 2010. to a total of three doses over 60 minutes. Available from: www.hbl.health.nz (Accessed Nov, 2012). 3. Ministry of Health (MOH). Guidelines for syringe driver Extra doses of antiemetics and other medicines in the management in palliative care in New Zealand. Wellington: syringe can also be given subcutaneously at the usual dose. If MOH; 2009. Available from: www.health.govt.nz (Accessed Nov, supplementary doses are required regularly for breakthrough 2012). symptoms, include these doses when calculating the amount 4. National Health Service (NHS). Guidelines for health professionals of medicine needed for the subsequent 24 hour period. If the in the community on the use of syringe drivers for adults in patient’s symptoms remain uncontrolled despite an increase palliative care. United Kingdom: NHS; 2010. Available from: www. in dose, consider an alternative medicine (e.g. because nausea oxfordshirepct.nhs.uk (Accessed Nov, 2012). may have many underlying causes it may be relieved by 5. National Health Service (NHS) Greater Glasgow Primary Care different medicines ) and consider a discussion with a palliative Palliative Care Team. Guidelines for the use of subcutaneous care physician. Also consider other methods to relieve a medications in palliative care for adults - primary care and hospices. Glasgow: NHS; 2010. Available from: www.nhsggc.org. patient’s distress – sometimes taking the time to sit and listen uk (Accessed Nov, 2012). can be as effective as administering a medicine. 6. Te Omanga Hospice. Te Omanga Hospice syringe driver protocol. Lower Hutt; 2011. Available from: www.teomanga.org.nz (Accessed Nov, 2012). Further resources 7. MacLeod R, Vella-Brincat J, Macleod S. The palliative care General Practitioners and other carers can access 24-hour handbook. 6th Edition. Hospice New Zealand; 2012. telephone help from their nearest hospice: www.hospice.org.nz/find-your-local-hospice-service

The Palliative Care Handbook, Guidelines for clinical management and symptom control. 6th Edition, 2012 is available as a printed copy (yellow book) free-of-charge from any hospice or download an electronic version from: www.hospice.org.nz

ACKNOWLEDGEMENT Thank you to Suzanne Brocx, Palliative Care Specialist Nurse Educator/Advisor, North Haven Hospice, Whangarei and Helen Cleaver, Palliative Care Clinical Nurse Specialist, Southern DHB, Dunedin for expert guidance in developing this article.

BPJ Issue 48 35 Initiating interventions in people with intermediate hyperglycaemia (“pre-diabetes”)

Intermediate hyperglycaemia is a state of raised glycaemic levels in a person without diabetes. It is an independent risk-factor for type 2 diabetes and cardiovascular disease. The primary aim of management of intermediate hyperglycaemia is to prevent progression to diabetes. Intervention involves structured lifestyle changes, and for people with a high risk of progression to diabetes who do not achieve normoglycaemia, treatment with metformin.

36 What constitutes intermediate hyperglycaemia? What’s in a name? Intermediate

Diabetes is diagnosed with an HbA1c level of 50 mmol/ hyperglycaemia versus pre-diabetes mol or greater (and, if measured, a fasting blood glucose ≥7.0mmol/L).1, 2 This is the glycaemic level at which the The term pre-diabetes is controversial: in 1980 the World incidence of moderate diabetic retinopathy begins to rise Health Organisation (WHO) recommended against its exponentially.2 In an asymptomatic person, a result greater use as not all people with borderline glycaemic levels than 50 mmol/mol should be repeated to confirm the progress to diabetes. In 2006 the WHO again discouraged diagnosis. the use of the term pre-diabetes and instead suggested “intermediate hyperglycaemia” to signify impaired fasting Intermediate hyperglycaemia is a biochemical state in which glucose (IFG) and impaired glucose tolerance (IGT).3 The a person has glucose levels above the normal range, but does 2012 NICE guidelines (United Kingdom) refer to “increased not yet meet the criteria for a diagnosis of diabetes. In New risk of type 2 diabetes” rather than pre-diabetes.4

Zealand intermediate hyperglycaemia is defined as an HbA1c level of 41 – 49 mmol/mol (and, if measured, a fasting blood glucose of 6.1 – 6.9 mmol/L).1, 2

Unlike diabetes, repeat testing is not required to confirm Intermediate hyperglycaemia is an intermediate hyperglycaemia. A single HbA result between 1c independent risk-factor for diabetes 41 – 49 mmol/mol in a person who is not acutely ill or who * does not have a condition that may affect HbA1c levels is Approximately 5 – 10% of people with intermediate sufficient. HbA1c should then be monitored every six to 12 hyperglycaemia progress to diabetes every year, but 5 – 10% months, unless there are intervening symptoms.2 will revert back to normogylcaemia.5, 6 However, in the long- term, up to 70% of people with intermediate hyperglycaemia 7 HbA1c is most frequently requested in the context of a will eventually develop type 2 diabetes. This represents cardiovascular disease (CVD) risk assessment. If a person is a relative risk for type 2 diabetes six times greater for identified as having intermediate hyperglycaemia, and they people with intermediate hyperglycaemia than those with are in the targeted age range, they should have a full CVD risk normogylcaemia.5 assessment, including investigation of lipid levels, if this was not done at the same time as the HbA1c test. Intermediate hyperglycaemia should be viewed as a continuous scale rather than a discrete variable, i.e. those at

In New Zealand, normoglycaemia is defined as an HbA1c level the higher end of the 41 – 49 mmol/mol range have a much below 40 mmol/mol (and, if measured, a fasting blood glucose greater risk of developing diabetes than those at the lower ≤6.0mmol/L).1, 2 end. The risk of having a high glycaemic level remains, even for people who have undergone proven prevention such as For further information on the use of HbA to diagnose bariatric surgery.8 1c diabetes, see: “The new role of HbA1c in diagnosing type 2 diabetes”, BPJ 42 (Feb, 2012) and “Understanding the new In addition, other factors play an important part in assessing

HbA1c units for the diagnosis of Type 2 diabetes”, Braatvedt G an individual’s risk of progressing to diabetes, including: et al, NZMJ 2012;125(1362). Age Weight and BMI Physical activity * For example high red blood cell turnover, iron or B12 supplementation

or recent blood transfusion can falsely lower HbA1c levels and severe Diet anaemia, B12 or folate deficiency, chronic alcoholism, chronic renal Ethnicity – Māori, Pacific and South-Asian people have an failure or certain haemoglobinopathies can falsely raise HbA levels. 1c increased risk of diabetes

BPJ Issue 48 37 Smoking status – three-fold increase in risk of the risk of diabetes related complications. Intervention progression to diabetes with lifestyle changes, and initiation of metformin where Family history of diabetes appropriate, can reduce the number of people progressing to 6, 13 Increased blood pressure clinical diabetes by 30 – 60%. Treatment is considered to be both safe and cost-effective.13–15 Increased lipid levels Certain conditions, such as polycystic ovary syndrome The Diabetes Prevention Program, a large United States study (see sidebar) of early prevention, found that 5% of people in the lifestyle intervention group and 7.8% of people in the metformin group There are a number of tools for assessing who is at risk of (no lifestyle changes) developed clinical diabetes each year, developing diabetes, and helping to determine the pre-test compared to 11% of those in the placebo group (Figure 1).6 probability of a diagnosis in people who have not had a recent Lifestyle intervention was more advantageous than metformin

HbA1c test. The most practical tools incorporate information in people aged over 60 years and those with a lower body-mass readily available to primary care and have a high specificity index.6 People who achieved even one normoglycaemic result for future diabetes progression.9 These prediction tools have during the study period had a significantly lower long-term not been validated in high risk ethnicities in New Zealand, risk of progressing to diabetes.16 therefore a single tool cannot be recommended above any other for this population. However, viewing the patient’s risk In the Diabetes Prevention Program, women with a history of in light of the above risk factors is likely to be beneficial in gestational diabetes and current intermediate hyperglycaemia assessing the likelihood of progression to diabetes. showed significant benefit from both lifestyle intervention and metformin. Each intervention reduced the relative risk of progression to diabetes by approximately 50% compared Many vascular complications begin before HbA reaches 1c with the placebo group. In contrast, this reduction was 49% for “diabetic” levels lifestyle and 14% for metformin in women without a history of While diabetes is defined by the threshold where the gestational diabetes.17 prevalence of moderate diabetic retinopathy begins to increase exponentially, many of the underlying Overall, it is estimated that the number of people with pathophysiological processes associated with diabetes intermediate hyperglycaemia who need to be treated for three begin during the intermediate hyperglycaemic stage. This years in order to prevent one case of diabetes is 6.9 for lifestyle includes nephropathy, chronic kidney disease, neuropathy, intervention and 13.9 for metformin.6 retinopathy, cardiovascular disease and overall mortality.10 Similarly, increased vascular risk remains even in people with Treatment goal: agree on a target HbA level diabetes who have achieved target glycaemic levels below the 1c diagnostic threshold for diabetes.11 There is no defined treatment target in people with intermediate hyperglycaemia, therefore a target should Early management is particularly important among high- be individually agreed upon between the patient and the risk groups as complications develop earlier, often before a doctor. Ideally the goal of treatment should be regression to

diagnosis of diabetes is made, although this could be a result normoglycaemia, in which case an HbA1c target of < 40 mmol/ of either lower testing rates (meaning longer unmanaged time mol should be aimed for, as this is associated with significant with hyperglycaemia) or a greater actual risk. For example, in a reductions in long-term diabetes risk.15 However, for many New Zealand study of 4269 Māori, of the participants identified people delaying and slowing the progression to diabetes is a as having clinical diabetes, 29.6% already had established more realistic target and is still likely to be beneficial. microalbuminuria, and 7.7% albuminuria, at diagnosis.12

Repeat testing of HbA1c is recommended every 6 – 12 months, unless there are intervening symptoms.20 Management of intermediate hyperglycaemia reduces progression to N.B It is critical that HbA1c level targets are not the only goal set, diabetes weight loss and exercise goals should be part of the treatment The identification and management of people with process. intermediate hyperglycaemia should be viewed as an opportunity to halt progression to diabetes and to reduce

38 BPJ Issue 48 40 Placebo

30 Metformin

20 Lifestyle

10

Cumulative Incidence of Diabetes (%) 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Time (Years)

Figure 1: The cumulative incidence of diabetes based on intervention6

Lifestyle intervention for everyone Some practices may consider addressing lifestyle interventions Most people with raised glycaemic levels will benefit from with patients in a group setting. Key components of a advice on an intensive programme of lifestyle changes.4 successful programme include:4 The two most important modifiable risk factors for diabetes Participants meet at least eight times over 9 – 18 months development are obesity and physical inactivity.7 Target goals Participants have at least 16 hours of educational time, should be set for weight, weekly physical activity level and diet, either in the group or on a one-to-one basis e.g. fat intake, fibre intake and total kilojoules. Follow-up sessions should be offered regularly, e.g. every Key advice includes encouraging people to:4 three months, for at least two years after the programme Undertake a minimum of 150 minutes of “moderate Behavioural change techniques should be used in intensity” physical activity per week conjunction with diet and exercise advice, e.g. setting Gradually lose weight to reach and maintain a BMI within short and long-term goals, identifying triggers the healthy range Increase consumption of whole grains, vegetables and Referral to a dietitian for further advice and guidance is likely other foods that are high in dietary fibre to be beneficial, although waiting times for publically funded Reduce the total amount of fat in their diet services and the cost of private services may be an issue for Eat less saturated fat some people.

In the Finnish Diabetes Prevention study, achievement of For further information on lifestyle interventions see: lifestyle intervention goals resulted in a reduction of 58% in “Addressing weight issues in young people and families in New the risk of progression to diabetes.18 Achieving each individual Zealand”. BPJ 45 (Aug, 2012) and “Promoting healthy lifestyles goal (e.g. exercise, reducing fat in the diet) was independently for Pacific peoples” BPJ 32 (Nov, 2010). associated with reduced risk of progression to diabetes. For example, a 5% reduction in weight significantly reduced the overall risk of developing diabetes (odds ratio of 0.3 compared Add metformin if lifestyle intervention is insufficient to no weight loss).18 In the Diabetes Prevention Program study After approximately six months of lifestyle intervention, people population, it was found that even a small weight loss, e.g. 1 who do not show glycaemic improvement, gain weight or kg, resulted in a significant reduction in the risk of progression are unable to adhere to recommendations may be offered to diabetes.6 metformin as an adjunct to lifestyle intervention.

BPJ Issue 48 39 In addition, most women with polycystic ovary syndrome and raised glycaemic levels are likely to benefit from a trial The role of metformin in women with with metformin (see “The role of metformin in women with polycystic ovary syndrome polycystic ovary syndrome”).19 Women with a history of Polycystic ovary syndrome (PCOS) is a group of disorders gestational diabetes and current intermediate hyperglycaemia that result in inappropriate gonadotropin secretion, are also likely to particularly benefit from metformin.17 usually from the ovaries but technically from anywhere along the hypothalamic-pituitary-ovarian (HPO) axis. It Because the benefits of metformin are not maintained after is common, affecting between 5 – 10% of women of cessation, it is important that diet and lifestyle management reproductive age.19 is continued during metformin treatment in order to address and improve the underlying obesogenic behaviours that The syndrome is characterised by a varying combination contribute to intermediate hyperglycaemia and diabetes. of menstrual dysfunction (typically oligo-ovulation Long-term primary prevention can then be maintained even or anovulation manifested by oligoamenorrhea), after medicine cessation. hyperandrogenism and polycystic ovaries on ultrasound. Insulin resistance is common in women with PCOS, along with an increased risk of developing type 2 diabetes How to prescribe metformin for intermediate hyperglycaemia and cardiovascular disease. Annual HbA1c testing is recommended, but there is very little evidence for Intermediate hyperglycaemia is not an approved use for measurement of plasma insulin in women with PCOS. metformin, but it can be prescribed fully subsidised for this indication and there is strong clinical evidence to justify its The role of metformin in women with PCOS is controversial. use. Metformin is potentially useful for maintaining satisfactory glycaemic levels and in increasing fertility, although Metformin can be commenced at a low dose, e.g. 500 mg evidence of effect has been difficult to find until recently. once daily, and increased gradually, e.g. over several weeks, as The PCOSMIC trial, a New Zealand trial investigating the tolerated to a maximum of 2 g daily if required.4 use of metformin and clomiphene in women with PCOS, found that metformin increased the pregnancy rate, and Lactic acidosis has been reported in people taking metformin that clomiphene plus metformin was more effective than who have reduced renal function. Although the risk may be either metformin or clomiphene alone.21 A long-term overstated, at present it is recommended that the dose of United States study found that metformin improved the metformin should be reduced if renal function deteriorates, metabolic profile of women with PCOS over a 36-month and people who decline to an eGFR < 30 mL/min/1.73m2 treatment course, particularly improving circulating HDL- or are at risk of rapid decline in renal function should cease cholesterol, diastolic blood pressure and BMI.19 treatment.1 A Cochrane review of 96,295 patients found no incidences of lactic acidosis in people taking metformin, even At present, there is no recommendation to treat all in those who had a contraindication to metformin, such as women with PCOS with metformin, nor is it an approved renal insufficiency.22 indication for metformin. However, women with PCOS and an HbA1c level > 40 mmol/mol are likely to benefit from Consider a maximum daily dose of 1 g metformin in patients use of metformin, in addition to lifestyle interventions. with eGFR 30–60 mL/min/1.73m2. However, in patients who are obese, eGFR may be an underestimate of their true creatinine clearance, and this group is likely to benefit most from metformin. Therefore metformin doses may not have to be reduced in obese patients with eGFR in the 45–60 mL/ min/1.73m2 range. If required, consider using the Cockcroft- Gault equation to calculate a more accurate value for creatinine clearance in these patients.

As metformin is primarily cleared by the kidneys, all patients taking metformin should have their renal function monitored annually and more frequently if clinically indicated.

40 BPJ Issue 48 the Australian Diabetes Society and Australian Diabetes Educators For further information on eGFR and kidney disease, see “Making a difference in chronic kidney disease”. BPJ 22 Association. Med J Aust 2007;186(9):461–5. (Jul, 2012) and “Acute-on-chronic kidney disease: prevention, 6. Diabetes Prevention Program Research Group. Reduction in the diagnosis, management and referral in primary care”, BPJ 46 incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403. (Sept, 2012). 7. Tabák AG, Herder C, Rathmann W, et al. Prediabetes: a high-risk state for diabetes development. The Lancet 2012;379(9833):2279–90. Compliance and adverse effects of metformin need to be 8. Carlsson L, Peltonen M, Ahlin S, et al. Bariatric surgery and prevention monitored of type 2 diabetes in Swedish obese subjects. N Eng J Med 2012;367:695–704. Metformin is generally well tolerated. The most common 9. Abbasi A, Peelen L, Corpeleijn E, et al. Prediction models for risk reported adverse effect is gastrointestinal disturbance. Other of developing type 2 diabetes: systematic literature search and adverse effects include anorexia, nausea, taste disturbance independent external validation study. BMJ 2012;345:e5900. and decreased vitamin-B12 absorption. 10. Bertram MY, Vos T. Quantifying the duration of pre-diabetes. Aust NZ J Publ Heal 2010;34(3):311–4. Regularly follow-up to ensure that metformin is being taken 11. Sarwar N, Gao P, Seshasai S, et al. Diabetes mellitus, fasting blood as prescribed and that adverse effects are not affecting glucose concentration, and risk of vascular disease: a collaborative adherence. meta-analysis of 102 prospective studies. Lancet 2010;375(9733):2251– 22. 12. Simmons D, Rush E, Crook N. Prevalence of undiagnosed diabetes, Metformin may need to be continued long-term impaired glucose tolerance, and impaired fasting glucose among Maori in Te Wai o Rona: Diabetes Prevention Strategy. N Z Med J 4 Metformin should be given initially for six to 12 months. For 2009;122(1288):30–8. many people metformin will need to be continued long-term. 13. Gillies C, Abrams K, Lambert P, et al. Pharmacological and lifestyle If no effect is seen with metformin, consider stopping the interventions to prevent or delay type 2 diabetes in people with medicine, but continue with lifestyle interventions.4 If, despite impaired glucose tolerance: systematic review and meta analysis. BMJ metformin treatment, the patient progresses to diabetes, 2007;334:299. other medicines, e.g. sulphonylureas or insulin, may need 14. Fradkin J, Robberts B, Rodgers G. What’s preventing us from preventing to be added if glycaemic control cannot be achieved with type 2 diabetes? N Engl J Med 2012;367:1177–9. metformin alone. 15. Bertram M, Lim S, Barendregt J, Vos T. Assessing the cost-effectiveness of drug and lifestyle intervention following opportunistic screening for pre-diabetes in primary care. Diabetologia 2010;53(5):875–81. ACKNOWLEDGEMENT: Thank you to Dr Brandon 16. Perreault L, Pan Q, Mather KJ, et al. Effect of regression from prediabetes Orr-Walker, Endocrinologist, Middlemore Hospital, to normal glucose regulation on long-term reduction in diabetes risk: Auckland and Dr Kirsten Coppell, Senior Research results from the Diabetes Prevention Program Outcomes Study. The Fellow, Edgar National Centre for Diabetes Research, Lancet 2012;379(9833):2243–51. Dunedin School of Medicine, University of Otago for 17. Ratner R, Christophi C, Metzger B, et al. Prevention of diabetes in expert guidance in developing this article. women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008;93(12):4774–9. 18. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of Type 2 References diabetes mellitus by changes in lifestyle among subjects with impaired 1. New Zealand Gudelines Group. New Zealand primary care handbook glucose tolerance. N Eng J Med 2001;344(18):1343–50. 2012. 3rd ed. Wellington: New Zealand Guidelines Group; 2012. 19. Lucidi R. Polycystic Ovarian Syndrome. Medscape Reference; 2012. 2. New Zealand Society for the Study of Diabetes (NZSSD). NZSSD Available from: http://emedicine.medscape.com/article/256806/ position statement on the diagnosis of, and screening for, Type 2 (Accessed Nov, 2012). diabetes. NZSSD; 2011. Available from: www.nzssd.org.nz (Accessed 20. Braatvedt G, Cundy T, Crooke M, et al. Understanding the new HbA1c Nov, 2012). units for the diagnosis of Type 2 diabetes. N Z Med J 2012;125(1362):In 3. World Health Organisation (WHO). Definition and diagnosis of press. diabetes mellitus and intermediate hyperglycaemia: report of a WHO/ 21. Johnson N, Stewart A, Falkiner J, et al. PCOSMIC: a multi-centre IDF consultation. WHO, Geneva; 2006. Available from: www.who.int randomized trial in women with Polycystic Ovary Syndrome (Accessed Nov, 2012). evaluating metformin for infertility with clomiphene. Hum Reprod 4. Chatterton H, Younger T, Fischer A, et al. Risk identification and 2010;25(7):1675–83. interventions to prevent type 2 diabetes in adults at high risk: 22. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and summary of NICE guidance. BMJ 2012;345:e4624. nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. 5. Twigg S, Kamp M, Davis T, et al. Prediabetes: a position statement from Cochrane Database Syst Rev 2010. 2010;(4):CD002967.

BPJ Issue 48 41 Are you getting the most you can from the New Zealand Formulary? Resources for getting started

The NZF offers several downloadable resources for understanding how to use the formulary and for teaching others. These are available from: www.nzformulary.org

Getting started expert-reviewed, general and specialised information under Although the NZF has been developed to be logical and headings such as: intuitive for users, a few minutes spent finding out more about Drugs in sport its features will enhance your ability to find the information Excipients you seek within the website. Māori health Drugs and driving Enter www.nzformulary.org and click on “User Information”. Prescribing in dental practice Prescribing in hepatic impairment Tutorial videos Links to websites of New Zealand healthcare groups and The full NZF tutorial video plays for approximately 12 minutes. professional organisations, and regulatory websites also Shorter video excerpts show examples of how to search and appear in this section and throughout the NZF. navigate within the online NZF, how monographs are laid out and how to use the interactions function for best results. The section titled “Calculators” enables you to enter specific patient information to calculate body mass index, body Before viewing the tutorial video, ensure there is a video player surface area, creatinine clearance, height conversion (feet to programme installed on the computer/device you are using. metres) and pregnancy due dates. The video can be expanded to fill the screen by clicking on the white arrows at the top right corner of the black side bar strip. Presentation slides for users The NZF tutorial slide show presents the main features of the The “Guidance on medicines use” section at the front of the NZF website in a format that can be viewed at the users own formulary is also explained in the tutorial. This section contains pace with simple, clear instructions.

42 BPJ Issue 48 www.bestpractice.net.nz

Frequently Asked Questions

A look at “Frequently asked questions” is a quick way of learning about some very useful features of the NZF, e.g. how to install the NZF icon on your MedTech Toolbar.

A commonly asked question is: When will there be an NZF app? The NZF team are currently investigating the development of an iPhone/iPad and android portable application.

In the meantime, the NZF eBook can be used on mobile devices. An eBook can be downloaded from the opening page of the NZF website. It is important to register to receive notifications of e-book updates.

Internet Explorer Compatibility Some issues with display of the left hand navigation menu have been reported for older Internet Explorer browsers. This issue is being investigated and a solution is being developed. FAST If you are using an IE6, IE7 or IE8 browser and experiencing issues please consider upgrading to a later version of Internet CVD QUICK SCREEN Explorer or an alternative browser such as Firefox or Chrome.

Feedback to the NZF The bestpractice CVD Quick Screen module is designed for speed — only data essential to the Feedback is monitored daily and all suggestions for changes Framingham equation is required and much of this and improvements to the NZF are considered by the can be pre-populated from the PMS. The result — a CVD Risk determined in seconds. production team. This includes both technological and content enhancements. Features include: Continued feedback is welcome; use the “Feedback” tab alongside the “Search” and “Browse” tabs at the top of each ■ Faster CVD Risk calculation page of the online version of NZ. Include a contact email ■ Heart Forecast tool integration address to ensure you receive a personal reply. ■ Saves a copy in the PMS ■ PPP compliant ■ Handles non-fasting bloods

See www.bestpractice.net.nz for more information about this and other bestpractice modules. Simply click the “All about modules” link on the Features tab.

Visit: www.nzformulary.org bestpractice DECISION SUPPORT FOR HEALTH PROFESSIONALS

bestpractice Decision Support is developed by BPAC Inc, which is separate from bpacnz. bpacnz bears no responsibility for bestpractice Decision Support or any use that is made of it.

BPJ Issue 48 43 CORRESPONDENCE

Recommended ceftriaxone dose for gonorrhoea References now 500 mg IM stat 1. New Zealand Sexual Health Society (NZSHS). Gonorrhoea. Best Practice Guidelines. NZSHS, 2009. Available from: www.nzshs.org/ treatment_guidelines/Gonorrhoea_2009.pdf (Accessed Nov, 2012). Dear Editor, I am writing regarding the treatment guideline for gonorrhoea 2. New Zealand Sexual Health Society (NZSHS). Gonorrhoea. Best Practice Guidelines. NZSHS, 2012. Available from: www.nzshs.org/guidelines/ which you recommend as ceftriaxone 250 mg stat (“Antibiotic Gonorrhoea-guideline.pdf (Accessed Nov, 2012). choices for common infections”, bpacnz 2011). Best practice 3. British Association for Sexual Health and HIV (BASHH). UK national guidelines on the Sexual Health Society website recommend guideline for the management of gonorrhoea in adults. BASHH, 2011. ceftriaxone 500 mg. This was reiterated by doctors from Auckland Available from: www.bashh.org/documents/3611 (Accessed Nov, Sexual Health, at a recent conference. I understand that 250 mg 2012). is acceptable but we mostly use 1 g vials, so it is easier and more 4. Institute of Environmental Science and Research Limited (ESR). Sexually accurate to reduce by half to 500 mg. transmitted infections in New Zealand. Annual Surveillance Report. ESR, 2011. Available from: www.surv.esr.cri.nz/PDF_surveillance/STIS Jody Macdonald, Clinical Nurse Specialist urvRpt/2011/2011AnnualSTIRpt.pdf (Accessed Nov, 2012). Palmerston North

The New Zealand Sexual Health Society has recently changed The role of digital rectal examination in prostate its recommendation for gonorrhoea treatment from 250 mg cancer follow-up ceftriaxone IM stat (in 2009),1 to 500mg IM stat (in 2012),2 given with azithromycin 1 g stat to cover concurrent chlamydia Dear Editor, infection. This increase in dose has been recommended to I am a little confused over a point made in your latest Best overcome emerging resistance of Neisseria gonorrhoeae Tests (Oct, 2012). I am sure I heard Dr Costello tell us on several to cephalosporins.3 It should be noted that although the occasions at the GP CME conference in Dunedin in August 2012, relevant subsidy requirement for ceftriaxone is “treatment of that 6 – 12 monthly DRE was still necessary in prostate cancer confirmed ciprofloxacin-resistant gonorrhoea”, the prevalence follow-up, no matter what the grade as there is a risk of the cancer of ciprofloxacin resistance is as high as 54% in some areas undifferentiating which makes PSA unreliable. in New Zealand.4 Ceftriaxone is available in 500 mg and 1 g Dr Phil White, General Practitioner formulations for injection. Dunedin

There is an update of recommendations for the treatment of sexual health conditions scheduled for Best Practice Journal in Dr Costello provided expert guidance in the development of 2013. This will include the following recommendations where our article: “Following up prostate cancer in primary care”, Best ceftriaxone is part of the treatment regimen: Tests (Oct, 2012). Most guidelines recommend that routine Gonorrhoea – ceftriaxone 500 mg IM, stat + azithromycin digital rectal examination (DRE) is generally not necessary 1 g stat in men where regular PSA testing indicates no change from Pelvic inflammatory disease – ceftriaxone 500 mg IM, baseline (but would be indicated if change occurred). DRE stat + doxycycline 100 mg, twice daily, for two weeks is not very useful after radical prostatectomy because early (or azithromycin 1 g stat, repeated in seven days) + local recurrence is not usually able to be felt. After radical metronidazole 400 mg, twice daily, for two weeks radiotherapy, it may be difficult to distinguish between scar tissue and residual or recurrent cancer. Therefore, DRE is Acute non-specific urethritis (with purulent discharge) - regarded as being of limited clinical value in these situations. ceftriaxone 500 mg IM, stat + azithromycin 1 g stat The exception is in men who have had high grade prostate Epididymo-orchitis (STI pathogens suspected) - cancers, i.e. Gleasons 9 and 10, where DRE may be of more ceftriaxone 500 mg IM, stat + doxycycline 100 mg, twice value as PSA may not be representative. This is an area of some daily, for at least two weeks disagreement, however, and guidelines do vary.

44 BPJ Issue 48 CORRESPONDENCE

There is some evidence that adding DRE to regular PSA testing Heterophile antibody vs EBV serology testing for for a small subset of patients with poorly differentiated, high glandular fever: Best Tests (Oct 2012) Gleason score prostate cancers may reduce prostate cancer related death.1 Routine DRE is not, however, necessary as part Dear Editor, of follow up in all men with prostate cancer. It is recognised A few months ago I was advised by the local lab not to order Paul- that poorly differentiated prostate cells leak PSA at a lower Bunnell or Monospot, i.e. heterophile antibodies, to aid glandular rate than well differentiated cancer cells. De-differentiation fever diagnosis because of its inaccuracy and they advised EBV (the change of cancer cells to a poorly differentiated state) serology instead. I am pretty certain there were no particular may lead to a slower rise in PSA level than the disease level features about the patient in question. might indicate. There have been cases studies illustrating Dr Phil White, General Practitioner the progression to metastatic disease without an elevation Dunedin in PSA level. It is estimated that the incidence of developing metastatic prostate cancer following radical prostatectomy, Firstly, if the patient has clear clinical features suggesting without a rise in PSA, is of the order of 2.3 – 2.6%.2, 3 It is also glandular fever, and no other complications, testing may not recognised that small cell prostatic cancer is not associated be necessary at all. with PSA expression. Heterophile antibody testing, most commonly with the It should be noted that there is a small potential for radical Monospot test, is highly accurate in a person with symptomatic, radiotherapy to induce rectal cancer after a period of years, suspected glandular fever when interpreted in conjunction therefore, there should be increased vigilance for this. with a full blood count. In a typical, symptomatic patient, heterophile antibodies have a high sensitivity and specificity. New Zealand-specific guidelines are likely to be produced soon The exception to this is in the first week of illness; if the patient as the Prostate Cancer Taskforce has now released a working has only recently developed symptoms then the sensitivity is consultation document, so recommendations may change in lower and false-negatives will occur in approximately 25% of the future. people. In this case EBV serology may be more appropriate. In addition, false-positives can occur in people with other ACKNOWLEDGEMENT: Thank you to Dr Shaun conditions, such as HIV. Costello, Radiation Oncologist, Clinical Director Southern Cancer Network for expert guidance in When taken in the context of the atypical antibody film from developing this response. the full blood count, the results of a Monospot are sufficiently accurate for most immunocompetent people (excluding References pregnant women and young children). As glandular fever is 1. Hattangadi J, Chen M, D’Amico A. Early detection of high-grade not a notifiable disease, is generally uncomplicated and has prostate cancer using digital rectal examination (DRE) in men with a life-time prevalence of 90%, more accurate testing (i.e. EBV a prostate-specific antigen level of <2.5 ng/mL and the risk of death. serology) is probably not necessary. BJU Int 2012;[Epub ahead of print].

2. Leibman B, Dillioglugil O, Wheeler T, Scardino T. Distant metastasis That being said, laboratories are not standardised across New after radical prostatectomy in patients without an elevated serum Zealand and individual requirements and recommendations prostate specific antigen level. Cancer 1995;76(12):2530-4. differ. While New Zealand and international guidance would 3. Oefelein M, Smith N, Carter M, et al. The incidence of prostate cancer indicate that heterophile testing plus atypical antibodies is progression with undetectable serum prostate specific antigen in a sufficient, if your local laboratory requires EBV serology, it is series of 394 radical prostatectomies. J Urol 1995;154(6):2128-31. best to adhere to their recommendations.

We value your feedback. Write to us at: Correspondence, PO Box 6032, Dunedin or email: [email protected]

45 visit us at www.bpac.org.nz Call us on 03 477 5418 Email us at [email protected] Freefax us on 0800 27 22 69